rs11542682

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_194454.3(KRIT1):c.1980A>G(p.Val660=) 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:9

Conservation

PhyloP100: -0.0620

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
KRIT1	NM_194454.3 linkuse as main transcript	c.1980A>G	p.Val660=	synonymous_variant	17/19	ENST00000394505.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRIT1	ENST00000394505.7 linkuse as main transcript	c.1980A>G	p.Val660=	synonymous_variant	17/19	1	NM_194454.3	P1	O00522-1

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

GnomAD3 exomes

AF:

0.127

AC:

31785

AN:

250970

Hom.:

2733

AF XY:

0.127

AC XY:

17262

AN XY:

135620

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 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.:

AF XY:

0.103

AC XY:

74705

AN XY:

726432

show subpopulations

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.:

AF XY:

0.117

AC XY:

8682

AN XY:

74370

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23485406, 20419355) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2017	- -

Cerebral cavernous malformation

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Angiokeratoma corporis diffusum with arteriovenous fistulas

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over