12-5044376-C-T

Position:

chr12-5044376-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002234.4(KCNA5):c.229C>T(p.Pro77Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,566,096 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P77A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00067 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

KCNA5
NM_002234.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.310

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048092604).

BP6

Variant 12-5044376-C-T is Benign according to our data. Variant chr12-5044376-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 469590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNA5	NM_002234.4 linkuse as main transcript	c.229C>T	p.Pro77Ser	missense_variant	1/1	ENST00000252321.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNA5	ENST00000252321.5 linkuse as main transcript	c.229C>T	p.Pro77Ser	missense_variant	1/1		NM_002234.4	P1	P22460-1

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00367

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00208

AC:

364

AN:

174728

Hom.:

AF XY:

0.00166

AC XY:

161

AN XY:

96704

show subpopulations

Gnomad AFR exome

AF:

0.000596

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00454

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.000333

AC:

471

AN:

1413764

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

204

AN XY:

700446

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.00863

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00276

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000640

Gnomad4 OTH exome

AF:

0.000273

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152332

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00368

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.00126

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000894

AC:

105

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Pulmonary arterial hypertension

Benign:1

Benign, no assertion criteria provided

clinical testing

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Sep 26, 2022

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

6.3

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0048

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

1.2

REVEL

Benign

0.23

Sift

Benign

0.31

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.15

MVP

0.96

MPC

0.53

ClinPred

0.0061

Varity_R

0.056

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over