7-92246090-T-TGAGCCG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_019004.2(ANKIB1):c.-504_-499dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 282,324 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: ANKIB1 NM_019004.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.798

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKIB1	NM_019004.2	c.-504_-499dup		5_prime_UTR_variant	1/20	ENST00000265742.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKIB1	ENST00000265742.8	c.-504_-499dup		5_prime_UTR_variant	1/20	1	NM_019004.2	P1

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151672 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000283 AC: 37 AN: 130538 Hom.: 0 Cov.: 0 AF XY: 0.000294 AC XY: 22 AN XY: 74956

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000318

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.000156

GnomAD4 genome AF: 0.000349 AC: 53 AN: 151786 Hom.: 1 Cov.: 31 AF XY: 0.000378 AC XY: 28 AN XY: 74136

Gnomad4 AFR AF: 0.000556

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Angiokeratoma corporis diffusum with arteriovenous fistulas Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cerebral cavernous malformation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886062498; hg19: chr7-91875404;