rs1057517753

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_194454.3(KRIT1):c.1201_1204delCAAA(p.Gln401ThrfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,096 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: 0.0000014 ( 0 hom. )

Consequence

KRIT1
NM_194454.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 9.54

Publications

3 publications found

Variant links:

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]

KRIT1 Gene-Disease associations (from GenCC):

cerebral cavernous malformation 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
famililal cerebral cavernous malformations
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRIT1 links:

ENSG00000289027 (HGNC:):

ENSG00000289027 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 7-92225769-TTTTG-T is Pathogenic according to our data. Variant chr7-92225769-TTTTG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 372398.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 link	c.1201_1204delCAAA	p.Gln401ThrfsTer10	frameshift_variant	Exon 12 of 19	ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KRIT1	ENST00000394505.7 link	c.1201_1204delCAAA	p.Gln401ThrfsTer10	frameshift_variant	Exon 12 of 19	1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1 link	c.1201_1204delCAAA	p.Gln401ThrfsTer10	frameshift_variant	Exon 12 of 26			ENSP00000510568.1
ENSG00000285953	ENST00000458493.6 link	c.1201_1204delCAAA	p.Gln401ThrfsTer10	frameshift_variant	Exon 11 of 20	4		ENSP00000396352.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459096

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

726050

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109686

Other (OTH)

AF:

0.00

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jul 18, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, 27649701, 22699465, 18300272, 20884211, 18383594, 33651268) -

Jun 14, 2016

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PP4, PM2, PS4_moderate, PVS1 -

Cerebral cavernous malformation

Pathogenic:2Uncertain:1

Oct 06, 2021

Laboratory of Medical Genetics, University of Torino

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln401Thrfs*10) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 2359550, 18300272, 20884211, 22699465, 27649701; internal data). This variant is also known as c.1197_1200delCAAA. ClinVar contains an entry for this variant (Variation ID: 372398). For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP4,PP5. -

Hereditary cavernous hemangioma of brain

Pathogenic:1

Jun 20, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.5

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over