Genetic Variant NM_194454.3:c.782C>T (chr7-92234871-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_194454.3(KRIT1):c.782C>T(p.Ser261Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KRIT1
NM_194454.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.51

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3983582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRIT1	NM_194454.3 link	c.782C>T	p.Ser261Leu	missense_variant	Exon 9 of 19	ENST00000394505.7	NP_919436.1	O00522-1A4D1F7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRIT1	ENST00000394505.7 link	c.782C>T	p.Ser261Leu	missense_variant	Exon 9 of 19	1	NM_194454.3	ENSP00000378013.2	O00522-1
ENSG00000289027	ENST00000692281.1 link	c.782C>T	p.Ser261Leu	missense_variant	Exon 9 of 26			ENSP00000510568.1	A0A8I5KWQ7
ENSG00000285953	ENST00000458493.6 link	c.782C>T	p.Ser261Leu	missense_variant	Exon 8 of 20	4		ENSP00000396352.2	C9JD81

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1456120

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33332

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106874

Other (OTH)

AF:

0.00

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;T;T;T;T;.;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D;.;.;.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.40

T;T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.6

.;L;L;L;L;L;.

PhyloP100

9.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.5

.;N;N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

.;D;D;D;D;D;D

Sift4G

Uncertain

0.015

.;D;D;D;D;D;.

Polyphen

0.48

.;P;P;P;P;.;.

Vest4

0.84, 0.84, 0.84, 0.70

MutPred

0.41

Gain of catalytic residue at S261 (P = 0.0069);Gain of catalytic residue at S261 (P = 0.0069);Gain of catalytic residue at S261 (P = 0.0069);Gain of catalytic residue at S261 (P = 0.0069);Gain of catalytic residue at S261 (P = 0.0069);Gain of catalytic residue at S261 (P = 0.0069);.;

MVP

0.71

MPC

0.63

ClinPred

0.95

GERP RS

5.0

Varity_R

0.33

gMVP

0.68

Mutation Taster

=60/40

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over