7-92246017-G-T

Variant names:

• chr7-92246017-G-T
• rs553392669
• NM_019004.2:c.-593G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_019004.2(ANKIB1):​c.-593G>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 0.0000191 in 104,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ANKIB1 NM_019004.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.415
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cerebral cavernous malformation 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289027 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019004.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKIB1	NM_019004.2	MANE Select	c.-593G>T		5_prime_UTR	Exon 1 of 20	NP_061877.1	Q9P2G1
	KRIT1	NM_001350672.1		c.-114C>A		5_prime_UTR	Exon 1 of 17	NP_001337601.1	O00522-1
	KRIT1	NM_001350673.1		c.-384C>A		5_prime_UTR	Exon 1 of 18	NP_001337602.1	O00522-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKIB1	ENST00000265742.8	TSL:1 MANE Select	c.-593G>T		5_prime_UTR	Exon 1 of 20	ENSP00000265742.3	Q9P2G1
	KRIT1	ENST00000340022.6	TSL:1	c.-936C>A		5_prime_UTR	Exon 1 of 19	ENSP00000344668.2	O00522-1
	KRIT1	ENST00000458177.7	TSL:1	c.-532C>A		5_prime_UTR	Exon 1 of 19	ENSP00000391675.2	O00522-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000191 AC: 2 AN: 104742 Hom.: 0 Cov.: 0 AF XY: 0.0000171 AC XY: 1 AN XY: 58634

African (AFR) AF: 0.00 AC: 0 AN: 488

American (AMR) AF: 0.00 AC: 0 AN: 550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2114

East Asian (EAS) AF: 0.00 AC: 0 AN: 382

South Asian (SAS) AF: 0.0000829 AC: 2 AN: 24132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 406

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63704

Other (OTH) AF: 0.00 AC: 0 AN: 5446

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.1
DANN	Benign	0.62
PhyloP100		0.41
PromoterAI		-0.11	Neutral
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 3

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

Other links and lift over

dbSNP: rs553392669; hg19: chr7-91875331;