19-49070200-T-A

Position:

• chr19-49070200-T-A

Variant summary

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

The NM_031886.3(KCNA7):​c.1234A>T​(p.Met412Leu) 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. 12/21 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)
• Consequence: KCNA7 NM_031886.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

Genes affected

KCNA7 (HGNC:6226): (potassium voltage-gated channel subfamily A member 7) 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. The gene is expressed preferentially in skeletal muscle, heart and kidney. It is a candidate gene for inherited cardiac disorders. [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=0.16299352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA7	NM_031886.3	c.1234A>T	p.Met412Leu	missense_variant	2/2	ENST00000221444.2	NP_114092.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA7	ENST00000221444.2	c.1234A>T	p.Met412Leu	missense_variant	2/2	1	NM_031886.3	ENSP00000221444.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

The c.1234A>T (p.M412L) alteration is located in exon 2 (coding exon 2) of the KCNA7 gene. This alteration results from a A to T substitution at nucleotide position 1234, causing the methionine (M) at amino acid position 412 to be replaced by a leucine (L). 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	0.082
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.37
Sift	Benign	0.069	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.33		Loss of disorder (P = 0.0997);
MVP		0.82
MPC		0.17
ClinPred		0.12	T
GERP RS		4.3
Varity_R		0.28
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49573457;