7-92234596-A-AT

Variant names:

• chr7-92234596-A-AT
• rs373763254
• ENST00000475770.6:n.1287dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000475770.6(KRIT1):​n.1287dupA variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,611,962 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: KRIT1 ENST00000475770.6 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.512
• Publications: 0 publications found

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

ENSG00000289027 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-92234596-A-AT is Benign according to our data. Variant chr7-92234596-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00213 (325/152302) while in subpopulation AFR AF = 0.00722 (300/41560). AF 95% confidence interval is 0.00655. There are 4 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 325 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000475770.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRIT1	NM_194454.3	MANE Select	c.846-5dupA		splice_region intron	N/A	NP_919436.1
	KRIT1	NM_001350672.1		c.846-5dupA		splice_region intron	N/A	NP_001337601.1
	KRIT1	NM_001350673.1		c.846-5dupA		splice_region intron	N/A	NP_001337602.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRIT1	ENST00000475770.6	TSL:1	n.1287dupA		non_coding_transcript_exon	Exon 1 of 10
	KRIT1	ENST00000394505.7	TSL:1 MANE Select	c.846-5dupA		splice_region intron	N/A	ENSP00000378013.2
	ENSG00000289027	ENST00000692281.1		c.846-5dupA		splice_region intron	N/A	ENSP00000510568.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152184 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000527 AC: 132 AN: 250642 AF XY: 0.000442

Gnomad AFR exome AF: 0.00706

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000243 AC: 355 AN: 1459660 Hom.: 2 Cov.: 30 AF XY: 0.000204 AC XY: 148 AN XY: 726328

African (AFR) AF: 0.00874 AC: 292 AN: 33420

American (AMR) AF: 0.000492 AC: 22 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110030

Other (OTH) AF: 0.000497 AC: 30 AN: 60328

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152302 Hom.: 4 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74468

African (AFR) AF: 0.00722 AC: 300 AN: 41560

American (AMR) AF: 0.000981 AC: 15 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00225

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation Benign:2

Mar 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KRIT1-related disorder Benign:1

Jul 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Angiokeratoma corporis diffusum with arteriovenous fistulas Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ENSG00000285953: BS2; ENSG00000289027: BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373763254; hg19: chr7-91863910;