rs6850768

Variant names:

• chr4-112797744-C-T
• rs6850768
• ENST00000503353.1:n.658G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000503353.1(ENSG00000250500):​n.658G>A 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 0.307 in 172,086 control chromosomes in the GnomAD database, including 8,289 homozygotes. 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: 𝑓 0.31 (7593 hom., cov: 32)
  • Exomes 𝑓: 0.26 (696 hom.)
• Consequence: ENSG00000250500 ENST00000503353.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 3 publications found

Genes affected

ENSG00000250500 (HGNC:58487):

ANK2 (HGNC:493): (ankyrin 2) This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2011]

ANK2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• cardiac arrhythmia, ankyrin-B-related

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2S3P2		n.112797744C>T		intragenic_variant
ANK2	NM_001386186.2	c.72+91527C>T		intron_variant	Intron 1 of 46		NP_001373115.1
ANK2	NM_001386148.2	c.72+91527C>T		intron_variant	Intron 1 of 45		NP_001373077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000250500	ENST00000503353.1	n.658G>A		non_coding_transcript_exon_variant	Exon 2 of 2	6

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47512 AN: 151858 Hom.: 7575 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.339

GnomAD4 exome AF: 0.262 AC: 5261 AN: 20110 Hom.: 696 Cov.: 0 AF XY: 0.265 AC XY: 3153 AN XY: 11878

African (AFR) AF: 0.321 AC: 183 AN: 570

American (AMR) AF: 0.260 AC: 598 AN: 2296

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 63 AN: 232

East Asian (EAS) AF: 0.314 AC: 467 AN: 1486

South Asian (SAS) AF: 0.251 AC: 510 AN: 2034

European-Finnish (FIN) AF: 0.302 AC: 510 AN: 1688

Middle Eastern (MID) AF: 0.322 AC: 342 AN: 1062

European-Non Finnish (NFE) AF: 0.240 AC: 2369 AN: 9858

Other (OTH) AF: 0.248 AC: 219 AN: 884

GnomAD4 genome AF: 0.313 AC: 47562 AN: 151976 Hom.: 7593 Cov.: 32 AF XY: 0.315 AC XY: 23354 AN XY: 74250

African (AFR) AF: 0.332 AC: 13761 AN: 41460

American (AMR) AF: 0.337 AC: 5143 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1081 AN: 3462

East Asian (EAS) AF: 0.349 AC: 1802 AN: 5164

South Asian (SAS) AF: 0.320 AC: 1542 AN: 4812

European-Finnish (FIN) AF: 0.338 AC: 3558 AN: 10526

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19655 AN: 67978

Other (OTH) AF: 0.343 AC: 724 AN: 2110

Alfa AF: 0.299 Hom.: 2617

Bravo AF: 0.316

Asia WGS AF: 0.392 AC: 1363 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.5
DANN	Benign	0.32
PhyloP100		2.1

Splicing

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

Other links and lift over

dbSNP: rs6850768; hg19: chr4-113718900;