rs41278788

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_194454.3(KRIT1):c.1245T>G(p.Ile415Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,543,714 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I415F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 8 hom. )

Consequence

KRIT1
NM_194454.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.148

Publications

2 publications found

Variant links:

Genes affected

KRIT1 (HGNC:1573): (KRIT1 ankyrin repeat containing) This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

KRIT1 Gene-Disease associations (from GenCC):

cerebral cavernous malformation 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
famililal cerebral cavernous malformations
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRIT1 links:

ENSG00000289027 (HGNC:):

ENSG00000289027 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065103173).

BP6

Variant 7-92225729-A-C is Benign according to our data. Variant chr7-92225729-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00185 (282/152260) while in subpopulation NFE AF = 0.00143 (97/68008). AF 95% confidence interval is 0.0012. There are 2 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRIT1	NM_194454.3 link	c.1245T>G	p.Ile415Met	missense_variant	Exon 12 of 19	ENST00000394505.7	NP_919436.1	O00522-1A4D1F7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRIT1	ENST00000394505.7 link	c.1245T>G	p.Ile415Met	missense_variant	Exon 12 of 19	1	NM_194454.3	ENSP00000378013.2	O00522-1
ENSG00000289027	ENST00000692281.1 link	c.1245T>G	p.Ile415Met	missense_variant	Exon 12 of 26			ENSP00000510568.1	A0A8I5KWQ7
ENSG00000285953	ENST00000458493.6 link	c.1245T>G	p.Ile415Met	missense_variant	Exon 11 of 20	4		ENSP00000396352.2	C9JD81

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

282

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00239

AC:

601

AN:

251212

AF XY:

0.00231

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00156

AC:

2177

AN:

1391454

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1033

AN XY:

696572

show subpopulations

African (AFR)

AF:

0.0000624

AC:

AN:

32074

American (AMR)

AF:

0.0000896

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25726

East Asian (EAS)

AF:

0.00

AC:

AN:

39320

South Asian (SAS)

AF:

0.000318

AC:

AN:

84790

European-Finnish (FIN)

AF:

0.0152

AC:

811

AN:

53306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5052

European-Non Finnish (NFE)

AF:

0.00119

AC:

1244

AN:

1048510

Other (OTH)

AF:

0.00152

AC:

AN:

58020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

190

286

381

476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00185

AC:

282

AN:

152260

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41568

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0162

AC:

172

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000714

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00223

AC:

271

EpiCase

AF:

0.000981

EpiControl

AF:

0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebral cavernous malformation

Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 15, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Angiokeratoma corporis diffusum with arteriovenous fistulas

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Jul 10, 2016

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Benign

3.9

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.11

.;T;T;T;T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.75

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.80

T;T;.;.;.;T

MetaRNN

Benign

0.0065

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N;N;N;.

PhyloP100

-0.15

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.48

.;N;N;N;N;N

REVEL

Benign

0.027

Sift

Benign

0.082

.;T;T;T;T;T

Sift4G

Benign

0.16

.;T;T;T;T;T

Polyphen

0.17

.;B;B;B;B;.

Vest4

0.18, 0.25, 0.21, 0.21, 0.15

MVP

0.60

MPC

0.31

ClinPred

0.0060

GERP RS

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.35

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over