1-110673174-G-A

Position:

• chr1-110673174-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002232.5(KCNA3):​c.1636C>T​(p.Pro546Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNA3 NM_002232.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

KCNA3 (HGNC:6221): (potassium voltage-gated channel subfamily A member 3) 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 belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. It plays an essential role in T-cell proliferation and activation. This gene appears to be intronless and it is clustered together with KCNA2 and KCNA10 genes on chromosome 1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12776977).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA3	NM_002232.5	c.1636C>T	p.Pro546Ser	missense_variant	1/1	ENST00000369769.4	NP_002223.3
KCNA3	NR_109845.2	n.218+63C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA3	ENST00000369769.4	c.1636C>T	p.Pro546Ser	missense_variant	1/1		NM_002232.5	ENSP00000358784	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.1636C>T (p.P546S) alteration is located in exon 1 (coding exon 1) of the KCNA3 gene. This alteration results from a C to T substitution at nucleotide position 1636, causing the proline (P) at amino acid position 546 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.12	N
MutationTaster	Benign	0.57	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.22
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.029	B
Vest4		0.15
MutPred		0.17		Loss of catalytic residue at P546 (P = 0.0702);
MVP		0.55
ClinPred		0.21	T
GERP RS		5.0
Varity_R		0.072
gMVP		0.44

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: rs145738982; hg19: chr1-111215796;