1-210683321-T-A

Variant names:

• chr1-210683321-T-A
• rs1334977288
• NM_172362.3:c.2930A>T

Variant summary

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

The NM_172362.3(KCNH1):​c.2930A>T​(p.Gln977Leu) 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. 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. Q977R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH1 NM_172362.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96

Genes affected

KCNH1 (HGNC:6250): (potassium voltage-gated channel subfamily H member 1) 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. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [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 the KCNH1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 72 curated benign missense variants. Gene score misZ: 3.8156 (above the threshold of 3.09). Trascript score misZ: 5.0674 (above the threshold of 3.09). GenCC associations: The gene is linked to KCNH1 associated disorder, Zimmermann-Laband syndrome, Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11579549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH1	NM_172362.3	c.2930A>T	p.Gln977Leu	missense_variant	Exon 11 of 11	ENST00000271751.10	NP_758872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10	c.2930A>T	p.Gln977Leu	missense_variant	Exon 11 of 11	2	NM_172362.3	ENSP00000271751.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;.;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.19	T;.;.;.
Sift4G	Benign	0.30	T;.;.;.
Polyphen		0.0040	B;.;.;.
Vest4		0.25
MutPred		0.18		Loss of solvent accessibility (P = 0.0098);.;.;.;
MVP		0.94
MPC		0.16
ClinPred		0.30	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.14

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: rs1334977288; hg19: chr1-210856663;