1-210728117-C-T

Variant names:

• chr1-210728117-C-T
• rs1953951
• NM_172362.3:c.2113-43979G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172362.3(KCNH1):​c.2113-43979G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 152,048 control chromosomes in the GnomAD database, including 14,901 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (14901 hom., cov: 33)
• Consequence: KCNH1 NM_172362.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.433
• Publications: 1 publications found

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]

KCNH1 Gene-Disease associations (from GenCC):

• KCNH1 associated disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina
• Temple-Baraitser syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• Zimmermann-Laband syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Zimmermann-Laband syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC105372901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH1	NM_172362.3	c.2113-43979G>A		intron_variant	Intron 10 of 10	ENST00000271751.10	NP_758872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10	c.2113-43979G>A		intron_variant	Intron 10 of 10	2	NM_172362.3	ENSP00000271751.4

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66528 AN: 151930 Hom.: 14884 Cov.: 33

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.449

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.438 AC: 66597 AN: 152048 Hom.: 14901 Cov.: 33 AF XY: 0.436 AC XY: 32422 AN XY: 74332

African (AFR) AF: 0.490 AC: 20288 AN: 41442

American (AMR) AF: 0.456 AC: 6968 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1409 AN: 3466

East Asian (EAS) AF: 0.245 AC: 1270 AN: 5174

South Asian (SAS) AF: 0.399 AC: 1921 AN: 4820

European-Finnish (FIN) AF: 0.384 AC: 4060 AN: 10580

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29348 AN: 67974

Other (OTH) AF: 0.450 AC: 950 AN: 2112

Alfa AF: 0.434 Hom.: 61014

Bravo AF: 0.448

Asia WGS AF: 0.359 AC: 1250 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.5
DANN	Benign	0.74
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1953951; hg19: chr1-210901459; COSMIC: COSV55098924;