19-49070868-G-C

Variant names:

• chr19-49070868-G-C
• rs1611775
• NM_031886.3:c.566C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (11617 hom., cov: 31)
  • Exomes 𝑓: 0.36 (94182 hom.)
• Consequence: KCNA7 NM_031886.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• Publications: 18 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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	c.566C>G	p.Pro189Arg	missense_variant	Exon 2 of 2	ENST00000221444.2	NP_114092.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58858 AN: 151920 Hom.: 11609 Cov.: 31

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

GnomAD2 exomes AF: 0.361 AC: 89615 AN: 248022 AF XY: 0.356

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 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.: 38 AF XY: 0.355 AC XY: 257657 AN XY: 725878

African (AFR) AF: 0.466 AC: 15591 AN: 33444

American (AMR) AF: 0.374 AC: 16674 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 7953 AN: 26014

East Asian (EAS) AF: 0.334 AC: 13227 AN: 39660

South Asian (SAS) AF: 0.323 AC: 27795 AN: 86080

European-Finnish (FIN) AF: 0.347 AC: 18486 AN: 53232

Middle Eastern (MID) AF: 0.291 AC: 1657 AN: 5690

European-Non Finnish (NFE) AF: 0.359 AC: 398428 AN: 1110418

Other (OTH) AF: 0.351 AC: 21168 AN: 60292

GnomAD4 genome AF: 0.387 AC: 58913 AN: 152038 Hom.: 11617 Cov.: 31 AF XY: 0.386 AC XY: 28697 AN XY: 74338

African (AFR) AF: 0.469 AC: 19431 AN: 41456

American (AMR) AF: 0.370 AC: 5644 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1077 AN: 3470

East Asian (EAS) AF: 0.342 AC: 1764 AN: 5160

South Asian (SAS) AF: 0.322 AC: 1552 AN: 4822

European-Finnish (FIN) AF: 0.347 AC: 3669 AN: 10588

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.362 AC: 24625 AN: 67970

Other (OTH) AF: 0.357 AC: 751 AN: 2104

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	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.36
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.043	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.79	N
PhyloP100		0.16
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.23
Sift	Benign	0.72	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.19
ClinPred		0.00036	T
GERP RS		3.5
Varity_R		0.028
gMVP		0.68
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1611775; hg19: chr19-49574125; COSMIC: COSV107283736;