dbSNP rs34358665: KRIT1:p.Arg26Gln (chr7-92242059-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_004912.4(KRIT1):c.77G>A(p.Arg26Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00133 in 1,576,640 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 4 hom. )

Consequence

KRIT1
NM_004912.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.48

Publications

9 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=0.014538407).

BP6

Variant 7-92242059-C-T is Benign according to our data. Variant chr7-92242059-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360890.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 = 0.000909 (138/151844) while in subpopulation NFE AF = 0.00143 (97/67958). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 138 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004912.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRIT1	NM_194454.3	MANE Select	c.77G>A	p.Arg26Gln	missense	Exon 4 of 19	NP_919436.1
KRIT1	NM_001350672.1		c.77G>A	p.Arg26Gln	missense	Exon 2 of 17	NP_001337601.1
KRIT1	NM_001350673.1		c.77G>A	p.Arg26Gln	missense	Exon 3 of 18	NP_001337602.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRIT1	ENST00000394505.7	TSL:1 MANE Select	c.77G>A	p.Arg26Gln	missense	Exon 4 of 19	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1		c.77G>A	p.Arg26Gln	missense	Exon 4 of 26	ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	TSL:4	c.77G>A	p.Arg26Gln	missense	Exon 3 of 20	ENSP00000396352.2

Frequencies

GnomAD3 genomes

AF:

0.000909

AC:

138

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000591

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00104

AC:

261

AN:

251236

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00137

AC:

1955

AN:

1424796

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

939

AN XY:

711434

show subpopulations

African (AFR)

AF:

0.000490

AC:

AN:

32680

American (AMR)

AF:

0.000716

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00344

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

39422

South Asian (SAS)

AF:

0.00

AC:

AN:

85278

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00161

AC:

1737

AN:

1078716

Other (OTH)

AF:

0.00127

AC:

AN:

59140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

166

249

332

415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.000909

AC:

138

AN:

151844

Hom.:

Cov.:

AF XY:

0.000823

AC XY:

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

41334

American (AMR)

AF:

0.000591

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

67958

Other (OTH)

AF:

0.00240

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.00140

Hom.:

Bravo

AF:

0.000888

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00101

AC:

122

EpiCase

AF:

0.00142

EpiControl

AF:

0.000949

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cerebral cavernous malformation (3)

not provided (2)

Angiokeratoma corporis diffusum with arteriovenous fistulas (1)

KRIT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.048

MetaRNN

Benign

0.015

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.6

PhyloP100

4.5

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.27

REVEL

Benign

0.16

Sift

Benign

0.14

Sift4G

Benign

0.077

Polyphen

0.91

Vest4

0.21

MVP

0.87

MPC

0.35

ClinPred

0.024

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.30

Mutation Taster

=82/18

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over