1-210683340-A-G

Position:

• chr1-210683340-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_172362.3(KCNH1):​c.2911T>C​(p.Phe971Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F971C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KCNH1 NM_172362.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.80

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 Likely_benign. 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), KCNH1. . Gene score misZ: 3.8156 (greater than the threshold 3.09). Trascript score misZ: 5.0674 (greater than threshold 3.09). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 72 curated benign missense variants. GenCC has associacion of the gene with KCNH1 associated disorder, Zimmermann-Laband syndrome, Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2259017).
• BP6: Variant 1-210683340-A-G is Benign according to our data. Variant chr1-210683340-A-G is described in ClinVar as [Benign]. Clinvar id is 1598978.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH1	NM_172362.3	c.2911T>C	p.Phe971Leu	missense_variant	11/11	ENST00000271751.10	NP_758872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10	c.2911T>C	p.Phe971Leu	missense_variant	11/11	2	NM_172362.3	ENSP00000271751.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461886 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.037	D;.;.;.
Sift4G	Benign	0.49	T;.;.;.
Polyphen		0.25	B;.;.;.
Vest4		0.13
MutPred		0.16		Loss of glycosylation at S974 (P = 0.2162);.;.;.;
MVP		0.97
MPC		0.20
ClinPred		0.65	D
GERP RS		2.7
Varity_R		0.096
gMVP		0.27

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: rs1681319929; hg19: chr1-210856682;