rs200684252

chr7-92235622-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_194454.3(KRIT1):c.510A>G(p.Gln170=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: KRIT1 NM_194454.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.82

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 7-92235622-T-C is Benign according to our data. Variant chr7-92235622-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 263101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92235622-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000177 (27/152280) while in subpopulation NFE AF= 0.000265 (18/68018). AF 95% confidence interval is 0.000171. There are 1 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRIT1	NM_194454.3	c.510A>G	p.Gln170=	synonymous_variant	8/19	ENST00000394505.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRIT1	ENST00000394505.7	c.510A>G	p.Gln170=	synonymous_variant	8/19	1	NM_194454.3	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251372 Hom.: 1 AF XY: 0.000118 AC XY: 16 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000978 AC: 143 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74 AN XY: 727102

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000544

Gnomad4 NFE exome AF: 0.0000863

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.0000907

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cerebral cavernous malformation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.82
Dann	Benign	0.42

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: rs200684252; hg19: chr7-91864936;