chr4-113049603-C-T

Variant names:

• chr4-113049603-C-T
• rs80077887
• ENST00000506722.5:c.22-124813C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001354225.2(ANK2):​c.-126C>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 0.012 in 1,506,396 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (150 hom.)
• Consequence: ANK2 NM_001354225.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.00
• Publications: 2 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-AS1 (HGNC:40076): (ANK2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 4-113049603-C-T is Benign according to our data. Variant chr4-113049603-C-T is described in ClinVar as Benign. ClinVar VariationId is 1253934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00817 (1244/152248) while in subpopulation SAS AF = 0.017 (82/4824). AF 95% confidence interval is 0.014. There are 10 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1244 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354225.2. 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
	ANK2	NM_001354225.2		c.-126C>T		5_prime_UTR	Exon 1 of 47	NP_001341154.1
	ANK2	NM_001354228.2		c.-126C>T		5_prime_UTR	Exon 1 of 46	NP_001341157.1	A0A5F9ZH70
	ANK2	NM_001354232.2		c.-126C>T		5_prime_UTR	Exon 1 of 47	NP_001341161.1	A0A5F9ZI81

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000506722.5	TSL:1	c.22-124813C>T		intron	N/A	ENSP00000421067.1	Q01484-5
	ANK2	ENST00000672502.1		c.-126C>T		5_prime_UTR	Exon 1 of 45	ENSP00000499870.1	I6L894
	ANK2	ENST00000672251.1		c.-126C>T		5_prime_UTR	Exon 1 of 44	ENSP00000500580.1	A0A5F9ZHT8

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152130 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.0125 AC: 16873 AN: 1354148 Hom.: 150 Cov.: 29 AF XY: 0.0127 AC XY: 8477 AN XY: 666896

African (AFR) AF: 0.00182 AC: 56 AN: 30834

American (AMR) AF: 0.00334 AC: 116 AN: 34780

Ashkenazi Jewish (ASJ) AF: 0.00553 AC: 132 AN: 23854

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 34020

South Asian (SAS) AF: 0.0157 AC: 1225 AN: 78114

European-Finnish (FIN) AF: 0.00880 AC: 317 AN: 36012

Middle Eastern (MID) AF: 0.0105 AC: 56 AN: 5314

European-Non Finnish (NFE) AF: 0.0137 AC: 14462 AN: 1055394

Other (OTH) AF: 0.00910 AC: 508 AN: 55826

GnomAD4 genome AF: 0.00817 AC: 1244 AN: 152248 Hom.: 10 Cov.: 32 AF XY: 0.00799 AC XY: 595 AN XY: 74446

African (AFR) AF: 0.00265 AC: 110 AN: 41538

American (AMR) AF: 0.00386 AC: 59 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4824

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 825 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.0105 Hom.: 11

Bravo AF: 0.00727

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.87
PhyloP100		1.0
PromoterAI		-0.13	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs80077887; hg19: chr4-113970759;