7-92236488-T-C

Variant names:

• chr7-92236488-T-C
• rs137853139
• NM_194454.3:c.410A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_194454.3(KRIT1):​c.410A>G​(p.Asp137Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRIT1 NM_194454.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.51

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 7-92236488-T-C is Pathogenic according to our data. Variant chr7-92236488-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.410A>G	p.Asp137Gly	missense_variant	Exon 7 of 19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.410A>G	p.Asp137Gly	missense_variant	Exon 7 of 19	1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1	c.410A>G	p.Asp137Gly	missense_variant	Exon 7 of 26			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	c.410A>G	p.Asp137Gly	missense_variant	Exon 6 of 20	4		ENSP00000396352.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation Pathogenic:2

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 137 of the KRIT1 protein (p.Asp137Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral cavernous malformations (PMID: 11914398, 11941540; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5725). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KRIT1 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 06, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A functional study confirmed the activation of a cryptic splice site (PMID: 11941540). Criteria applied: PS3, PS4_SUP, PM2_SUP, PP3 -

Cerebral cavernous malformation 1 Pathogenic:1

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;D;D;D;D;.;T;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.;.;.;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	2.0	.;M;M;M;M;M;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.0	.;N;N;N;N;N;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.024	.;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D;.;.
Polyphen		1.0	.;D;D;D;D;.;.;.;.
Vest4		0.92, 0.94, 0.98, 0.95, 0.95
MutPred		0.86		Gain of catalytic residue at C134 (P = 0.1116);Gain of catalytic residue at C134 (P = 0.1116);Gain of catalytic residue at C134 (P = 0.1116);Gain of catalytic residue at C134 (P = 0.1116);Gain of catalytic residue at C134 (P = 0.1116);Gain of catalytic residue at C134 (P = 0.1116);Gain of catalytic residue at C134 (P = 0.1116);Gain of catalytic residue at C134 (P = 0.1116);Gain of catalytic residue at C134 (P = 0.1116);
MVP		0.94
MPC		1.1
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.40
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137853139; hg19: chr7-91865802;