rs1934620

Variant names:

• chr1-210724921-A-G
• rs1934620
• NM_172362.3:c.2113-40783T>C

Variant summary

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

The NM_172362.3(KCNH1):​c.2113-40783T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,110 control chromosomes in the GnomAD database, including 2,832 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 0.18 (2832 hom., cov: 32)
• Consequence: KCNH1 NM_172362.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.852
• Publications: 7 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=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH1	NM_172362.3	c.2113-40783T>C		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.2113-40783T>C		intron_variant	Intron 10 of 10	2	NM_172362.3	ENSP00000271751.4

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27902 AN: 151992 Hom.: 2825 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0952

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.196

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

GnomAD4 genome AF: 0.184 AC: 27941 AN: 152110 Hom.: 2832 Cov.: 32 AF XY: 0.183 AC XY: 13645 AN XY: 74370

African (AFR) AF: 0.274 AC: 11374 AN: 41470

American (AMR) AF: 0.230 AC: 3517 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3464

East Asian (EAS) AF: 0.0949 AC: 492 AN: 5186

South Asian (SAS) AF: 0.144 AC: 693 AN: 4820

European-Finnish (FIN) AF: 0.128 AC: 1356 AN: 10592

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9448 AN: 67982

Other (OTH) AF: 0.196 AC: 413 AN: 2112

Alfa AF: 0.162 Hom.: 5883

Bravo AF: 0.197

Asia WGS AF: 0.155 AC: 539 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.66
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1934620; hg19: chr1-210898263; COSMIC: COSV55101625;