rs11542682

Variant names:

Variant summary

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

The NM_194454.3(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_194454.3 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRIT1	NM_194454.3 link	c.1980A>G	p.Val660Val	synonymous_variant	Exon 17 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.1980A>G	p.Val660Val	synonymous_variant	Exon 17 of 19	1	NM_194454.3	ENSP00000378013.2	O00522-1
ENSG00000289027	ENST00000692281.1 link	c.1980A>G	p.Val660Val	synonymous_variant	Exon 17 of 26			ENSP00000510568.1	A0A8I5KWQ7
ENSG00000285953	ENST00000458493.6 link	c.1980A>G	p.Val660Val	synonymous_variant	Exon 16 of 20	4		ENSP00000396352.2	C9JD81

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

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

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

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23485406, 20419355) -

Nov 24, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebral cavernous malformation

Benign:3

Mar 22, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Angiokeratoma corporis diffusum with arteriovenous fistulas

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

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

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rs11542682

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