7-92245996-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019004.2(ANKIB1):c.-614C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 234,902 control chromosomes in the GnomAD database, including 1,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (779 hom., cov: 31)
  • Exomes 𝑓: 0.097 (530 hom.)
• Consequence: ANKIB1 NM_019004.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0480

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-92245996-C-T is Benign according to our data. Variant chr7-92245996-C-T is described in ClinVar as [Benign]. Clinvar id is 360905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKIB1	NM_019004.2	c.-614C>T		5_prime_UTR_variant	1/20	ENST00000265742.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKIB1	ENST00000265742.8	c.-614C>T		5_prime_UTR_variant	1/20	1	NM_019004.2	P1

Frequencies

GnomAD3 genomes AF: 0.0857 AC: 13037 AN: 152086 Hom.: 778 Cov.: 31

Gnomad AFR AF: 0.0571

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0847

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0792

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0781

Gnomad OTH AF: 0.0930

GnomAD4 exome AF: 0.0967 AC: 7997 AN: 82698 Hom.: 530 Cov.: 0 AF XY: 0.105 AC XY: 4766 AN XY: 45508

Gnomad4 AFR exome AF: 0.0718

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.0710

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.0794

Gnomad4 NFE exome AF: 0.0803

Gnomad4 OTH exome AF: 0.0859

GnomAD4 genome AF: 0.0857 AC: 13043 AN: 152204 Hom.: 779 Cov.: 31 AF XY: 0.0901 AC XY: 6703 AN XY: 74406

Gnomad4 AFR AF: 0.0572

Gnomad4 AMR AF: 0.0818

Gnomad4 ASJ AF: 0.0847

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.0792

Gnomad4 NFE AF: 0.0780

Gnomad4 OTH AF: 0.0925

Alfa AF: 0.0579 Hom.: 79

Bravo AF: 0.0859

Asia WGS AF: 0.205 AC: 713 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2018

- -

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. -

Cerebral cavernous malformation 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	8.9
Dann	Benign	0.87

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: rs28365965; hg19: chr7-91875310; COSMIC: COSV56061339; COSMIC: COSV56061339;