chr1-110518027-T-C

Position:

• chr1-110518027-T-C

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.761A>G​(p.Asn254Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00563 in 1,613,658 control chromosomes in the GnomAD database, including 336 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (155 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (181 hom.)
• Consequence: KCNA10 NM_005549.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.118

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=0.0017726421).
• BP6: Variant 1-110518027-T-C is Benign according to our data. Variant chr1-110518027-T-C is described in ClinVar as [Benign]. Clinvar id is 775575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA10	NM_005549.2	c.761A>G	p.Asn254Ser	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.761A>G	p.Asn254Ser	missense_variant	1/1		NM_005549.2	ENSP00000358786	P1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3626 AN: 151676 Hom.: 149 Cov.: 31

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00357

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.00753 AC: 1893 AN: 251472 Hom.: 73 AF XY: 0.00614 AC XY: 835 AN XY: 135908

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00928

GnomAD4 exome AF: 0.00371 AC: 5427 AN: 1461864 Hom.: 181 Cov.: 34 AF XY: 0.00355 AC XY: 2582 AN XY: 727236

Gnomad4 AFR exome AF: 0.0859

Gnomad4 AMR exome AF: 0.00825

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00321

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00835

GnomAD4 genome AF: 0.0241 AC: 3655 AN: 151794 Hom.: 155 Cov.: 31 AF XY: 0.0237 AC XY: 1761 AN XY: 74172

Gnomad4 AFR AF: 0.0779

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00399

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00158

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.0133 Hom.: 52

Bravo AF: 0.0269

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0724 AC: 319

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00881 AC: 1070

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00379

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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.35
DANN	Benign	0.17
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.30
Sift	Benign	0.66	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.017
MVP		0.27
MPC		0.031
ClinPred		0.00086	T
GERP RS		3.9
Varity_R		0.030
gMVP		0.27

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: rs11806812; hg19: chr1-111060649;