7-92246005-T-C

Position:

• chr7-92246005-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_019004.2(ANKIB1):​c.-605T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00866 in 242,372 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (6 hom., cov: 31)
  • Exomes 𝑓: 0.010 (3 hom.)
• Consequence: ANKIB1 NM_019004.2 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.395

Genes affected

ANKIB1 (HGNC:22215): (ankyrin repeat and IBR domain containing 1) Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Predicted to be involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; protein polyubiquitination; and ubiquitin-dependent protein catabolic process. Predicted to be part of ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-92246005-T-C is Benign according to our data. Variant chr7-92246005-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 360906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKIB1	NM_019004.2	c.-605T>C		5_prime_UTR_variant	1/20	ENST00000265742.8	NP_061877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKIB1	ENST00000265742	c.-605T>C		5_prime_UTR_variant	1/20	1	NM_019004.2	ENSP00000265742.3

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1181 AN: 151978 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.00463

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00863

GnomAD4 exome AF: 0.0101 AC: 916 AN: 90276 Hom.: 3 Cov.: 0 AF XY: 0.0101 AC XY: 503 AN XY: 49958

Gnomad4 AFR exome AF: 0.00995

Gnomad4 AMR exome AF: 0.00711

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00753

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.00931

GnomAD4 genome AF: 0.00777 AC: 1182 AN: 152096 Hom.: 6 Cov.: 31 AF XY: 0.00714 AC XY: 531 AN XY: 74338

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00463

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.00985 Hom.: 1

Bravo AF: 0.00773

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Angiokeratoma corporis diffusum with arteriovenous fistulas Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

ANKIB1: BS1, BS2; KRIT1: BS1, BS2 -

Cerebral cavernous malformation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.71

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: rs143215997; hg19: chr7-91875319;