rs886041209

Positions:

• chr7-92241100-ACTTT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_194454.3(KRIT1):​c.151_154del​(p.Lys51PhefsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRIT1 NM_194454.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.03

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 18 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 7-92241100-ACTTT-A is Pathogenic according to our data. Variant chr7-92241100-ACTTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 279827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92241100-ACTTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRIT1	NM_194454.3	c.151_154del	p.Lys51PhefsTer13	frameshift_variant	5/19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRIT1	ENST00000394505.7	c.151_154del	p.Lys51PhefsTer13	frameshift_variant	5/19	1	NM_194454.3	ENSP00000378013	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459252 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23595507, 12404106, 31254430, 30161288, 17043900) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2024

The c.151_154delAAAG (p.K51Ffs*13) alteration, located in exon 6 (coding exon 2) of the KRIT1 gene, consists of a deletion of 4 nucleotides from position 151 to 154, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with KRIT1-related cerebral cavernous malformations and cosegregates with disease in several families (Nardella, 2018; Riant, 2013; Cavé-Riant, 2002). Based on the available evidence, this alteration is classified as pathogenic. -

Cerebral cavernous malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279827). This premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 12404106, 30161288). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys51Phefs*13) in the KRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KRIT1 are known to be pathogenic (PMID: 10508515, 11222804, 12404106, 24689081). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886041209; hg19: chr7-91870414;