Genetic Variant KRIT1:p.Gln201Glu (chr7-92235531-G-C) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.60

Publications

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

KRIT1 links:

ENSG00000289027 (HGNC:):

ENSG00000289027 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 5726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194454.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRIT1	NM_194454.3	MANE Select	c.601C>G	p.Gln201Glu	missense	Exon 8 of 19	NP_919436.1	O00522-1
KRIT1	NM_001350672.1		c.601C>G	p.Gln201Glu	missense	Exon 6 of 17	NP_001337601.1	O00522-1
KRIT1	NM_001350673.1		c.601C>G	p.Gln201Glu	missense	Exon 7 of 18	NP_001337602.1	O00522-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRIT1	ENST00000394505.7	TSL:1 MANE Select	c.601C>G	p.Gln201Glu	missense	Exon 8 of 19	ENSP00000378013.2	O00522-1
ENSG00000289027	ENST00000692281.1		c.601C>G	p.Gln201Glu	missense	Exon 8 of 26	ENSP00000510568.1	A0A8I5KWQ7
ENSG00000285953	ENST00000458493.6	TSL:4	c.601C>G	p.Gln201Glu	missense	Exon 7 of 20	ENSP00000396352.2	C9JD81

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cerebral cavernous malformation (1)

Cerebral cavernous malformation 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

0.072

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.34

PhyloP100

9.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.92

REVEL

Benign

0.27

Sift

Benign

0.097

Sift4G

Benign

0.80

Polyphen

0.020

Vest4

0.77

MutPred

0.73

Gain of helix (P = 0.0078)

MVP

0.86

MPC

0.31

ClinPred

0.66

GERP RS

5.2

Varity_R

0.14

gMVP

0.71

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over