1-111776108-G-T

Position:

• chr1-111776108-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001378969.1(KCND3):​c.1937C>A​(p.Ala646Asp) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCND3 NM_001378969.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

Genes affected

KCND3 (HGNC:6239): (potassium voltage-gated channel subfamily D member 3) Voltage-gated potassium (Kv) 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, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCND3. . Gene score misZ 3.8545 (greater than the threshold 3.09). Trascript score misZ 4.8782 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 19/22, Brugada syndrome 1, Brugada syndrome 9.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13084632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.1937C>A	p.Ala646Asp	missense_variant	8/8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.1937C>A	p.Ala646Asp	missense_variant	8/8	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.1937C>A	p.Ala646Asp	missense_variant	8/8	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.1880C>A	p.Ala627Asp	missense_variant	6/6	1		ENSP00000358711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	.;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.0	.;N;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.070	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0090	.;B;.
Vest4		0.39
MutPred		0.21		.;Loss of MoRF binding (P = 0.0143);.;
MVP		0.28
MPC		0.99
ClinPred		0.51	D
GERP RS		4.7
Varity_R		0.23
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs910058506; hg19: chr1-112318730;