4-112904455-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The ENST00000506722.5(ANK2):c.-39G>C variant causes a splice region, 5 prime UTR 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 ENST00000506722.5 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.7931
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.71

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]

ACMG classification

Verdict is Benign. Variant got -8 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.
• BS2: High AC in GnomAd at 129 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001127493.3	c.-39G>C		splice_region_variant, 5_prime_UTR_variant	2/47
ANK2	NM_001354239.2	c.-39G>C		splice_region_variant, 5_prime_UTR_variant	2/49
ANK2	NM_001354243.2	c.-39G>C		splice_region_variant, 5_prime_UTR_variant	2/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000506722.5	c.-39G>C		splice_region_variant, 5_prime_UTR_variant	2/47	1
ANK2	ENST00000503271.5	c.-39G>C		splice_region_variant, 5_prime_UTR_variant	2/31	2
ANK2	ENST00000503423.6	c.-39G>C		splice_region_variant, 5_prime_UTR_variant	2/46	5		A2

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

GnomAD3 exomes AF: 0.00193 AC: 255 AN: 132364 Hom.: 3 AF XY: 0.00198 AC XY: 139 AN XY: 70244

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 SAS exome AF: 0.000234

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

Gnomad4 AFR exome AF: 0.000107

Gnomad4 AMR exome AF: 0.0000682

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000160

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00190

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

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00238

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

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs775400814; hg19: chr4-113825611;