12-5043981-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBA1

The NM_002234.4(KCNA5):c.-167C>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 0.411 in 691,452 control chromosomes in the GnomAD database, including 61,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 15301 hom., cov: 33)

Exomes 𝑓: 0.40 ( 45941 hom. )

Consequence

KCNA5
NM_002234.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.61

Publications

15 publications found

Variant links:

Genes affected

KCNA5 (HGNC:6224): (potassium voltage-gated channel subfamily A member 5) Potassium channels represent the most complex class of voltage-gated ino channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Defects in this gene are a cause of familial atrial fibrillation type 7 (ATFB7). [provided by RefSeq, May 2012]

KCNA5 Gene-Disease associations (from GenCC):

atrial fibrillation, familial, 7
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.13).

BP6

Variant 12-5043981-C-T is Benign according to our data. Variant chr12-5043981-C-T is described in ClinVar as Benign. ClinVar VariationId is 309329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA5	NM_002234.4 link	c.-167C>T		5_prime_UTR_variant	Exon 1 of 1	ENST00000252321.5	NP_002225.2	P22460-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA5	ENST00000252321.5 link	c.-167C>T		5_prime_UTR_variant	Exon 1 of 1	6	NM_002234.4	ENSP00000252321.3		P22460-1

Frequencies

GnomAD3 genomes

AF:

0.439

AC:

66650

AN:

151990

Hom.:

15282

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.448

Gnomad ASJ

AF:

0.410

Gnomad EAS

AF:

0.617

Gnomad SAS

AF:

0.557

Gnomad FIN

AF:

0.438

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.359

Gnomad OTH

AF:

0.402

GnomAD4 exome

AF:

0.404

AC:

217709

AN:

539344

Hom.:

45941

Cov.:

AF XY:

0.409

AC XY:

115866

AN XY:

283476

show subpopulations

African (AFR)

AF:

0.549

AC:

7469

AN:

13606

American (AMR)

AF:

0.431

AC:

8949

AN:

20768

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

5811

AN:

14522

East Asian (EAS)

AF:

0.560

AC:

17514

AN:

31266

South Asian (SAS)

AF:

0.545

AC:

26375

AN:

48376

European-Finnish (FIN)

AF:

0.437

AC:

12996

AN:

29748

Middle Eastern (MID)

AF:

0.381

AC:

838

AN:

2200

European-Non Finnish (NFE)

AF:

0.360

AC:

125825

AN:

349794

Other (OTH)

AF:

0.411

AC:

11932

AN:

29064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

6964

13928

20892

27856

34820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1734

3468

5202

6936

8670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.439

AC:

66708

AN:

152108

Hom.:

15301

Cov.:

AF XY:

0.444

AC XY:

33001

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.538

AC:

22338

AN:

41514

American (AMR)

AF:

0.448

AC:

6859

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.410

AC:

1421

AN:

3470

East Asian (EAS)

AF:

0.617

AC:

3168

AN:

5136

South Asian (SAS)

AF:

0.558

AC:

2684

AN:

4812

European-Finnish (FIN)

AF:

0.438

AC:

4635

AN:

10588

Middle Eastern (MID)

AF:

0.322

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.360

AC:

24437

AN:

67974

Other (OTH)

AF:

0.402

AC:

851

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1916

3832

5747

7663

9579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.378

Hom.:

18047

Bravo

AF:

0.440

Asia WGS

AF:

0.579

AC:

2009

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atrial fibrillation, familial, 7

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

1.6

PromoterAI

-0.036

Neutral

(source)

Mutation Taster

=292/8

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over