1-110673462-T-C

Variant names:

• chr1-110673462-T-C
• rs1651961819
• NM_002232.5:c.1348A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_002232.5(KCNA3):​c.1348A>G​(p.Met450Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M450L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNA3 NM_002232.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.01
• Publications: 0 publications found

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]

ENSG00000300042 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_002232.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.0156 (below the threshold of 3.09). Trascript score misZ: 2.8395 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002232.5. 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
	KCNA3	NM_002232.5	MANE Select	c.1348A>G	p.Met450Val	missense	Exon 1 of 1	NP_002223.3
	KCNA3	NR_109845.2		n.-8A>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA3	ENST00000369769.4	TSL:6 MANE Select	c.1348A>G	p.Met450Val	missense	Exon 1 of 1	ENSP00000358784.2	P22001-1
	KCNA3	ENST00000685980.2		n.1348A>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000513296.1	P22001-1
	KCNA3	ENST00000697409.1		n.1348A>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000513297.1	P22001-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	0.80	N
PhyloP100		8.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Polyphen		0.89	P
Vest4		0.82
MutPred		0.69		Gain of catalytic residue at M450 (P = 0.1562)
MVP		0.97
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.86
gMVP		0.98
Mutation Taster		=48/52	disease causing

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: rs1651961819; hg19: chr1-111216084;