rs11542682

Variant names:

• chr7-92213240-T-C
• rs11542682
• NM_194454.3:c.1980A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0620

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]

ENSG00000289027 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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. Variant chr7-92213240-T-C is described in Lovd as [Benign].
• 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	c.1980A>G	p.Val660Val	synonymous_variant	Exon 17 of 19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.1980A>G	p.Val660Val	synonymous_variant	Exon 17 of 19	1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1	c.1980A>G	p.Val660Val	synonymous_variant	Exon 17 of 26			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	c.1980A>G	p.Val660Val	synonymous_variant	Exon 16 of 20	4		ENSP00000396352.2

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17294 AN: 152010 Hom.: 1128 Cov.: 32

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

GnomAD3 exomes AF: 0.127 AC: 31785 AN: 250970 Hom.: 2733 AF XY: 0.127 AC XY: 17262 AN XY: 135620

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 SAS exome AF: 0.167

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.: 31 AF XY: 0.103 AC XY: 74705 AN XY: 726432

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.345

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.0866

Gnomad4 NFE exome AF: 0.0862

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.114 AC: 17304 AN: 152128 Hom.: 1131 Cov.: 32 AF XY: 0.117 AC XY: 8682 AN XY: 74370

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0999

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.0872

Gnomad4 NFE AF: 0.0909

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0999 Hom.: 1029

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

Submissions by phenotype

not provided Benign:4

Nov 24, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cerebral cavernous malformation Benign:3

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. -

Mar 22, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs11542682; hg19: chr7-91842554; COSMIC: COSV60666621;