Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004912.4(KRIT1):c.1980A>G(p.Val660Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,612,268 control chromosomes in the GnomAD database, including 10,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1131 hom., cov: 32)

Exomes 𝑓: 0.10 ( 9241 hom. )

Consequence

KRIT1
NM_004912.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0620

Publications

34 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 7-92213240-T-C is Benign according to our data. Variant chr7-92213240-T-C is described in ClinVar as Benign. ClinVar VariationId is 263098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.062 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

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.1980A>G	p.Val660Val	synonymous	Exon 17 of 19	NP_919436.1
KRIT1	NM_001350672.1		c.1980A>G	p.Val660Val	synonymous	Exon 15 of 17	NP_001337601.1
KRIT1	NM_001350673.1		c.1980A>G	p.Val660Val	synonymous	Exon 16 of 18	NP_001337602.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRIT1	ENST00000394505.7	TSL:1 MANE Select	c.1980A>G	p.Val660Val	synonymous	Exon 17 of 19	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1		c.1980A>G	p.Val660Val	synonymous	Exon 17 of 26	ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	TSL:4	c.1980A>G	p.Val660Val	synonymous	Exon 16 of 20	ENSP00000396352.2

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17294

AN:

152010

Hom.:

1128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.141

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.170

Gnomad FIN

AF:

0.0872

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0910

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.127

AC:

31785

AN:

250970

AF XY:

0.127

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.0998

Gnomad EAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.0844

Gnomad NFE exome

AF:

0.0947

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.101

AC:

146928

AN:

1460140

Hom.:

9241

Cov.:

AF XY:

0.103

AC XY:

74705

AN XY:

726432

show subpopulations

African (AFR)

AF:

0.126

AC:

4218

AN:

33436

American (AMR)

AF:

0.107

AC:

4792

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2646

AN:

26120

East Asian (EAS)

AF:

0.345

AC:

13674

AN:

39630

South Asian (SAS)

AF:

0.163

AC:

14015

AN:

86192

European-Finnish (FIN)

AF:

0.0866

AC:

4620

AN:

53358

Middle Eastern (MID)

AF:

0.110

AC:

636

AN:

5764

European-Non Finnish (NFE)

AF:

0.0862

AC:

95686

AN:

1110608

Other (OTH)

AF:

0.110

AC:

6641

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

6293

12587

18880

25174

31467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3644

7288

10932

14576

18220

<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:

0.114

AC:

17304

AN:

152128

Hom.:

1131

Cov.:

AF XY:

0.117

AC XY:

8682

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.127

AC:

5267

AN:

41486

American (AMR)

AF:

0.0999

AC:

1526

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

352

AN:

3468

East Asian (EAS)

AF:

0.356

AC:

1839

AN:

5172

South Asian (SAS)

AF:

0.170

AC:

819

AN:

4826

European-Finnish (FIN)

AF:

0.0872

AC:

923

AN:

10590

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0909

AC:

6184

AN:

67994

Other (OTH)

AF:

0.112

AC:

236

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

744

1488

2231

2975

3719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

206

412

618

824

1030

<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:

0.101

Hom.:

1298

Bravo

AF:

0.117

Asia WGS

AF:

0.211

AC:

734

AN:

3478

EpiCase

AF:

0.0955

EpiControl

AF:

0.0954

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Cerebral cavernous malformation (3)

not specified (2)

Angiokeratoma corporis diffusum with arteriovenous fistulas (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.5

(source)

DANN

Benign

0.62

PhyloP100

-0.062

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=92/8

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over