NM_002234.4:c.92G>T

Variant names:

• chr12-5044239-G-T
• rs61737395
• NM_002234.4:c.92G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002234.4(KCNA5):​c.92G>T​(p.Gly31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,539,188 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. G31A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (65 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (46 hom.)
• Consequence: KCNA5 NM_002234.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.437
• Publications: 3 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017237067).
• BP6: Variant 12-5044239-G-T is Benign according to our data. Variant chr12-5044239-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.015 (2282/152344) while in subpopulation AFR AF = 0.0508 (2114/41588). AF 95% confidence interval is 0.049. There are 65 homozygotes in GnomAd4. There are 1108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2282 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002234.4. 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
	KCNA5	NM_002234.4	MANE Select	c.92G>T	p.Gly31Val	missense	Exon 1 of 1	NP_002225.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA5	ENST00000252321.5	TSL:6 MANE Select	c.92G>T	p.Gly31Val	missense	Exon 1 of 1	ENSP00000252321.3	P22460-1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2276 AN: 152226 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00660

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00366 AC: 496 AN: 135632 AF XY: 0.00283

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.00173 AC: 2404 AN: 1386844 Hom.: 46 Cov.: 31 AF XY: 0.00152 AC XY: 1043 AN XY: 684660

African (AFR) AF: 0.0520 AC: 1649 AN: 31732

American (AMR) AF: 0.00271 AC: 97 AN: 35782

Ashkenazi Jewish (ASJ) AF: 0.00557 AC: 140 AN: 25152

East Asian (EAS) AF: 0.00 AC: 0 AN: 36002

South Asian (SAS) AF: 0.000290 AC: 23 AN: 79286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36554

Middle Eastern (MID) AF: 0.00353 AC: 17 AN: 4816

European-Non Finnish (NFE) AF: 0.000230 AC: 248 AN: 1079670

Other (OTH) AF: 0.00398 AC: 230 AN: 57850

GnomAD4 genome AF: 0.0150 AC: 2282 AN: 152344 Hom.: 65 Cov.: 33 AF XY: 0.0149 AC XY: 1108 AN XY: 74492

African (AFR) AF: 0.0508 AC: 2114 AN: 41588

American (AMR) AF: 0.00660 AC: 101 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68026

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00463 Hom.: 1

Bravo AF: 0.0168

ESP6500AA AF: 0.0335 AC: 129

ESP6500EA AF: 0.000389 AC: 3

ExAC AF: 0.00261 AC: 256

Asia WGS AF: 0.00520 AC: 18 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Atrial fibrillation, familial, 7 (3)
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0017	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.44
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.24
Sift	Benign	0.066	T
Sift4G	Benign	0.15	T
Polyphen		0.099	B
Vest4		0.083
MVP		0.99
MPC		0.70
ClinPred		0.0037	T
GERP RS		-0.27
PromoterAI		-0.018	Neutral
Varity_R		0.10
gMVP		0.34
Mutation Taster		=99/1	polymorphism

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: rs61737395; hg19: chr12-5153405;