4-112904455-G-C

Variant names:

• chr4-112904455-G-C
• rs775400814
• ENST00000506722.5:c.-39G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001386142.1(ANK2):​c.-39G>C variant causes a splice region change. The variant allele was found at a frequency of 0.000753 in 1,429,550 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (8 hom.)
• Consequence: ANK2 NM_001386142.1 splice_region
• Scores: Splicing: ADA: 0.7931
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.71
• Publications: 1 publications found

Genes affected

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=-0.21).
• BP6: Variant 4-112904455-G-C is Benign according to our data. Variant chr4-112904455-G-C is described in ClinVar as [Benign]. Clinvar id is 2655031.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000848 (129/152050) while in subpopulation NFE AF = 0.000397 (27/67960). AF 95% confidence interval is 0.00028. There are 1 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 129 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001386142.1	c.-39G>C		splice_region_variant	Exon 2 of 45		NP_001373071.1
ANK2	NM_001386143.1	c.-39G>C		splice_region_variant	Exon 2 of 48		NP_001373072.1
ANK2	NM_001354239.2	c.-39G>C		splice_region_variant	Exon 2 of 49		NP_001341168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000506722.5	c.-39G>C		splice_region_variant	Exon 2 of 47	1		ENSP00000421067.1
ANK2	ENST00000506722.5	c.-39G>C		5_prime_UTR_variant	Exon 2 of 47	1		ENSP00000421067.1
ANK2	ENST00000672209.1	c.-39G>C		splice_region_variant	Exon 2 of 48			ENSP00000499982.1

Frequencies

GnomAD3 genomes AF: 0.000849 AC: 129 AN: 151934 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00193 AC: 255 AN: 132364 AF XY: 0.00198

Gnomad AFR exome AF: 0.000287

Gnomad AMR exome AF: 0.0000547

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.000741 AC: 947 AN: 1277500 Hom.: 8 Cov.: 20 AF XY: 0.000762 AC XY: 483 AN XY: 633550

African (AFR) AF: 0.000107 AC: 3 AN: 27914

American (AMR) AF: 0.0000682 AC: 2 AN: 29332

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 623 AN: 23894

East Asian (EAS) AF: 0.00 AC: 0 AN: 33940

South Asian (SAS) AF: 0.000160 AC: 11 AN: 68636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48734

Middle Eastern (MID) AF: 0.00313 AC: 17 AN: 5428

European-Non Finnish (NFE) AF: 0.000192 AC: 189 AN: 985988

Other (OTH) AF: 0.00190 AC: 102 AN: 53634

GnomAD4 genome AF: 0.000848 AC: 129 AN: 152050 Hom.: 1 Cov.: 33 AF XY: 0.000834 AC XY: 62 AN XY: 74320

African (AFR) AF: 0.000121 AC: 5 AN: 41490

American (AMR) AF: 0.000393 AC: 6 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67960

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.00479 Hom.: 2

Bravo AF: 0.000929

Asia WGS AF: 0.000582 AC: 2 AN: 3448

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ANK2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.96
PhyloP100		5.7
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Benign	0.58

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

Other links and lift over

dbSNP: rs775400814; hg19: chr4-113825611;