12-4810060-C-G

Variant names:

• chr12-4810060-C-G
• rs372562061
• NM_002235.5:c.19C>G

Variant summary

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

The NM_002235.5(KCNA6):​c.19C>G​(p.Leu7Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNA6 NM_002235.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.529

Genes affected

KCNA6 (HGNC:6225): (potassium voltage-gated channel subfamily A member 6) 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. The coding region of this gene is intronless, and the gene is clustered with genes KCNA1 and KCNA5 on chromosome 12. [provided by RefSeq, Jul 2008]

GALNT8 (HGNC:4130): (polypeptide N-acetylgalactosaminyltransferase 8) This gene encodes a member of the UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase (GalNAc-T) family of enzymes. GalNAc-Ts initiate mucin-type O-linked glycosylation in the Golgi apparatus by catalyzing the transfer of GalNAc to serine and threonine residues on target proteins. They are characterized by an N-terminal transmembrane domain, a stem region, a lumenal catalytic domain containing a GT1 motif and Gal/GalNAc transferase motif, and a C-terminal ricin/lectin-like domain. GalNAc-Ts have different, but overlapping, substrate specificities and patterns of expression. [provided by RefSeq, Jul 2008]

ENSG00000256988 (HGNC:58276):

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=0.1759705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA6	NM_002235.5	c.19C>G	p.Leu7Val	missense_variant	Exon 1 of 1	ENST00000280684.4	NP_002226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA6	ENST00000280684.4	c.19C>G	p.Leu7Val	missense_variant	Exon 1 of 1	6	NM_002235.5	ENSP00000280684.3
GALNT8	ENST00000542998.5	c.310-40678C>G		intron_variant	Intron 3 of 3	3		ENSP00000440383.1
ENSG00000256988	ENST00000662877.1	n.410-3192G>C		intron_variant	Intron 2 of 2
ENSG00000256988	ENST00000664363.1	n.1626+3496G>C		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1392726 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 685834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.082	.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.60	.;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.69	.;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.34	T;T
Polyphen		0.063	.;B
Vest4		0.27
MutPred		0.17		Gain of MoRF binding (P = 0.0667);Gain of MoRF binding (P = 0.0667);
MVP		0.67
MPC		1.1
ClinPred		0.097	T
GERP RS		2.4
Varity_R		0.13
gMVP		0.45

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: rs372562061; hg19: chr12-4919226;