rs1554512658

Variant names:

• chr7-92221919-AG-A
• rs1554512658
• NM_194454.3:c.1545delC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_194454.3(KRIT1):​c.1545delC​(p.Leu516TrpfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRIT1 NM_194454.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.858

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-92221919-AG-A is Pathogenic according to our data. Variant chr7-92221919-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 468210.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.1545delC	p.Leu516TrpfsTer11	frameshift_variant	Exon 14 of 19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.1545delC	p.Leu516TrpfsTer11	frameshift_variant	Exon 14 of 19	1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1	c.1545delC	p.Leu516TrpfsTer11	frameshift_variant	Exon 14 of 26			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	c.1545delC	p.Leu516TrpfsTer11	frameshift_variant	Exon 13 of 20	4		ENSP00000396352.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral cavernous malformation Pathogenic:1

Jul 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KRIT1 are known to be pathogenic (PMID: 10508515, 11222804, 12404106). This variant has not been reported in the literature in individuals with KRIT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu516Trpfs*11) in the KRIT1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1554512658; hg19: chr7-91851233;