1-110518130-C-T

Position:

• chr1-110518130-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005549.2(KCNA10):​c.658G>A​(p.Val220Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0713 in 1,613,666 control chromosomes in the GnomAD database, including 4,459 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.060 (320 hom., cov: 30)
  • Exomes 𝑓: 0.073 (4139 hom.)
• Consequence: KCNA10 NM_005549.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.800

Genes affected

KCNA10 (HGNC:6219): (potassium voltage-gated channel subfamily A member 10) 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. It is specifically regulated by cGMP and postulated to mediate the effects of substances that increase intracellular cGMP. This gene is intronless, and the gene is clustered with genes KCNA2 and KCNA3 on chromosome 1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024356544).
• BP6: Variant 1-110518130-C-T is Benign according to our data. Variant chr1-110518130-C-T is described in ClinVar as [Benign]. Clinvar id is 1294562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA10	NM_005549.2	c.658G>A	p.Val220Met	missense_variant	1/1	ENST00000369771.4	NP_005540.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA10	ENST00000369771.4	c.658G>A	p.Val220Met	missense_variant	1/1		NM_005549.2	ENSP00000358786	P1

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9064 AN: 151668 Hom.: 319 Cov.: 30

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0502

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0749

Gnomad OTH AF: 0.0709

GnomAD3 exomes AF: 0.0684 AC: 17179 AN: 251332 Hom.: 654 AF XY: 0.0716 AC XY: 9720 AN XY: 135820

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.0352

Gnomad ASJ exome AF: 0.0482

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.0739

Gnomad OTH exome AF: 0.0706

GnomAD4 exome AF: 0.0725 AC: 106022 AN: 1461878 Hom.: 4139 Cov.: 73 AF XY: 0.0736 AC XY: 53497 AN XY: 727238

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.0476

Gnomad4 EAS exome AF: 0.0956

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.0547

Gnomad4 NFE exome AF: 0.0737

Gnomad4 OTH exome AF: 0.0700

GnomAD4 genome AF: 0.0597 AC: 9058 AN: 151788 Hom.: 320 Cov.: 30 AF XY: 0.0606 AC XY: 4494 AN XY: 74118

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.0508

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0502

Gnomad4 NFE AF: 0.0748

Gnomad4 OTH AF: 0.0711

Alfa AF: 0.0729 Hom.: 684

Bravo AF: 0.0574

TwinsUK AF: 0.0766 AC: 284

ALSPAC AF: 0.0778 AC: 300

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.0749 AC: 644

ExAC AF: 0.0699 AC: 8485

Asia WGS AF: 0.0870 AC: 301 AN: 3478

EpiCase AF: 0.0780

EpiControl AF: 0.0751

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 26108971) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.83	P
Vest4		0.030
MPC		0.036
ClinPred		0.012	T
GERP RS		4.1
Varity_R		0.099
gMVP		0.55

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

Other links and lift over

dbSNP: rs34970857; hg19: chr1-111060752; COSMIC: COSV63904576; COSMIC: COSV63904576;