7-92242059-C-T

Position:

chr7-92242059-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_194454.3(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_194454.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.48

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 -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 [Likely_benign]. Clinvar id is 360890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92242059-C-T is described in Lovd as [Likely_benign]. Variant chr7-92242059-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRIT1	NM_194454.3 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	4/19	ENST00000394505.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRIT1	ENST00000394505.7 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	4/19	1	NM_194454.3	P1	O00522-1

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

GnomAD3 exomes

AF:

0.00104

AC:

261

AN:

251236

Hom.:

AF XY:

0.00105

AC XY:

143

AN XY:

135792

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 SAS 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

Gnomad4 AFR exome

AF:

0.000490

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.00127

GnomAD4 genome

AF:

0.000909

AC:

138

AN:

151844

Hom.:

Cov.:

AF XY:

0.000823

AC XY:

AN XY:

74126

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.000591

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00143

Gnomad4 OTH

AF:

0.00240

Alfa

AF:

0.00153

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebral cavernous malformation

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Angiokeratoma corporis diffusum with arteriovenous fistulas

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

KRIT1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

.;T;T;T;T;.;T;T;.;T;.;T;T;T;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;.;.;.;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.015

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.6

.;L;L;L;L;L;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.27

.;N;N;N;N;N;N;N;N;N;N;N;N;D;D;D

REVEL

Benign

0.16

Sift

Benign

0.14

.;T;T;T;T;T;T;T;T;D;D;D;D;D;D;D

Sift4G

Benign

0.077

.;T;T;T;T;D;D;.;.;T;.;.;.;T;T;T

Polyphen

0.91

.;P;P;P;P;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.21, 0.22, 0.22, 0.21, 0.18

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

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