rs137853140

Positions:

• chr7-92235531-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_194454.3(KRIT1):​c.601C>G​(p.Gln201Glu) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRIT1 NM_194454.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76
• PP5: Variant 7-92235531-G-C is Pathogenic according to our data. Variant chr7-92235531-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 5726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.601C>G	p.Gln201Glu	missense_variant	8/19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.601C>G	p.Gln201Glu	missense_variant	8/19	1	NM_194454.3	ENSP00000378013	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2017

The Q201E variant has been published previously in association with familial cerebral cavernous malformation (CCM) (Verlaan et al., 2002; Battistini et al., 2007; Haghighi et al., 2013). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Q201E is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Several in-silico splice prediction models predict that c.601 C>G creates a cryptic donor site which supplants the natural donor site and leads to abnormal gene splicing. Additionally, RNA studies have shown the variant causes a portion of exon 9 (referred to as exon 8 in the publication) to be lost, resulting in a frameshift variant (Verlaan et al., 2002). In summary, we consider this variant to be pathogenic. -

Cerebral cavernous malformation 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Cerebral cavernous malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2023

ClinVar contains an entry for this variant (Variation ID: 5726). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 201 of the KRIT1 protein (p.Gln201Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cerebral cavernous malformations (PMID: 24007869). It has also been observed to segregate with disease in related individuals. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	.;T;T;T;T;.;T
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.;.;.;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.34	.;N;N;N;N;N;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.92	.;N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.097	.;T;T;T;T;T;T
Sift4G	Benign	0.80	.;T;T;T;T;T;T
Polyphen		0.020	.;B;B;B;B;.;.
Vest4		0.77, 0.77, 0.79, 0.78, 0.41
MutPred		0.73		Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);
MVP		0.86
MPC		0.31
ClinPred		0.66	D
GERP RS		5.2
Varity_R		0.14
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853140; hg19: chr7-91864845;