chr7-92225840-G-C

Variant names:

• chr7-92225840-G-C
• rs779465895
• NM_194454.3:c.1147-13C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_194454.3(KRIT1):​c.1147-13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRIT1 NM_194454.3 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0580

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-92225840-G-C is Pathogenic according to our data. Variant chr7-92225840-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 590691.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.1147-13C>G		intron_variant	Intron 11 of 18	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.1147-13C>G		intron_variant	Intron 11 of 18	1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1	c.1147-13C>G		intron_variant	Intron 11 of 25			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	c.1147-13C>G		intron_variant	Intron 10 of 19	4		ENSP00000396352.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KRIT1-related disorder Pathogenic:1

Feb 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KRIT1 c.1147-13C>G variant is predicted to interfere with splicing. This variant is predicted to interfere with splicing based on splicing prediction programs (Alamut Visual Plus v.1.6.1). This variant was reported in an individual with cerebral cavernous malformations, and functional analysis showed that it causes disrupted splicing and early protein termination (reported as IVS11-13 C>G in Marini et al 2003. PubMed ID: 12810002). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Cerebral cavernous malformation Pathogenic:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 12 of the KRIT1 gene. It does not directly change the encoded amino acid sequence of the KRIT1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cerebral cavernous malformations (PMID: 12810002; internal data). ClinVar contains an entry for this variant (Variation ID: 590691). Studies have shown that this variant results in a new splice acceptor site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12810002). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	12
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1
DS_AL_spliceai		0.94		Position offset: -13

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

Publications

LitVar

Other links and lift over

dbSNP: rs779465895; hg19: chr7-91855154;