Genetic Variant KCNA7:p.Pro189Arg (chr19-49070868-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_031886.3(KCNA7):c.566C>G(p.Pro189Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,611,406 control chromosomes in the GnomAD database, including 105,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.39 ( 11617 hom., cov: 31)

Exomes 𝑓: 0.36 ( 94182 hom. )

Consequence

KCNA7
NM_031886.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.164

Variant links:

Genes affected

KCNA7 (HGNC:6226): (potassium voltage-gated channel subfamily A member 7) Potassium channels represent the most complex class of voltage-gated ion 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. The gene is expressed preferentially in skeletal muscle, heart and kidney. It is a candidate gene for inherited cardiac disorders. [provided by RefSeq, Jul 2008]

KCNA7 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012057722).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA7	NM_031886.3 link	c.566C>G	p.Pro189Arg	missense_variant	Exon 2 of 2	ENST00000221444.2	NP_114092.2	Q96RP8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA7	ENST00000221444.2 link	c.566C>G	p.Pro189Arg	missense_variant	Exon 2 of 2	1	NM_031886.3	ENSP00000221444.1		Q96RP8

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58858

AN:

151920

Hom.:

11609

Cov.:

show subpopulations

Gnomad AFR

AF:

0.469

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.370

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.342

Gnomad SAS

AF:

0.322

Gnomad FIN

AF:

0.347

Gnomad MID

AF:

0.293

Gnomad NFE

AF:

0.362

Gnomad OTH

AF:

0.357

GnomAD3 exomes

AF:

0.361

AC:

89615

AN:

248022

Hom.:

16529

AF XY:

0.356

AC XY:

47836

AN XY:

134202

show subpopulations

Gnomad AFR exome

AF:

0.465

Gnomad AMR exome

AF:

0.383

Gnomad ASJ exome

AF:

0.305

Gnomad EAS exome

AF:

0.341

Gnomad SAS exome

AF:

0.326

Gnomad FIN exome

AF:

0.342

Gnomad NFE exome

AF:

0.362

Gnomad OTH exome

AF:

0.347

GnomAD4 exome

AF:

0.357

AC:

520979

AN:

1459368

Hom.:

94182

Cov.:

AF XY:

0.355

AC XY:

257657

AN XY:

725878

show subpopulations

Gnomad4 AFR exome

AF:

0.466

Gnomad4 AMR exome

AF:

0.374

Gnomad4 ASJ exome

AF:

0.306

Gnomad4 EAS exome

AF:

0.334

Gnomad4 SAS exome

AF:

0.323

Gnomad4 FIN exome

AF:

0.347

Gnomad4 NFE exome

AF:

0.359

Gnomad4 OTH exome

AF:

0.351

GnomAD4 genome

AF:

0.387

AC:

58913

AN:

152038

Hom.:

11617

Cov.:

AF XY:

0.386

AC XY:

28697

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.469

Gnomad4 AMR

AF:

0.370

Gnomad4 ASJ

AF:

0.310

Gnomad4 EAS

AF:

0.342

Gnomad4 SAS

AF:

0.322

Gnomad4 FIN

AF:

0.347

Gnomad4 NFE

AF:

0.362

Gnomad4 OTH

AF:

0.357

Alfa

AF:

0.341

Hom.:

6711

Bravo

AF:

0.391

TwinsUK

AF:

0.348

AC:

1292

ALSPAC

AF:

0.354

AC:

1365

ESP6500AA

AF:

0.461

AC:

2030

ESP6500EA

AF:

0.345

AC:

2966

ExAC

AF:

0.365

AC:

44281

Asia WGS

AF:

0.346

AC:

1205

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.36

DEOGEN2

Benign

0.22

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.043

MetaRNN

Benign

0.0012

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.79

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.65

REVEL

Benign

0.23

Sift

Benign

0.72

Sift4G

Benign

0.59

Polyphen

0.0

Vest4

0.030

MPC

0.19

ClinPred

0.00036

GERP RS

3.5

Varity_R

0.028

gMVP

0.68

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over