NM_172362.3:c.1463-16887A>G

Variant names:

• chr1-210821053-T-C
• rs1112269
• NM_172362.3:c.1463-16887A>G

Variant summary

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

The NM_172362.3(KCNH1):​c.1463-16887A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,174 control chromosomes in the GnomAD database, including 4,068 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 0.22 (4068 hom., cov: 32)
• Consequence: KCNH1 NM_172362.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 4 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH1	NM_172362.3	c.1463-16887A>G		intron_variant	Intron 7 of 10	ENST00000271751.10	NP_758872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10	c.1463-16887A>G		intron_variant	Intron 7 of 10	2	NM_172362.3	ENSP00000271751.4

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33302 AN: 152056 Hom.: 4069 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.219 AC: 33310 AN: 152174 Hom.: 4068 Cov.: 32 AF XY: 0.224 AC XY: 16643 AN XY: 74378

African (AFR) AF: 0.136 AC: 5640 AN: 41536

American (AMR) AF: 0.208 AC: 3178 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1101 AN: 3472

East Asian (EAS) AF: 0.493 AC: 2546 AN: 5166

South Asian (SAS) AF: 0.352 AC: 1695 AN: 4820

European-Finnish (FIN) AF: 0.242 AC: 2564 AN: 10576

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15810 AN: 67990

Other (OTH) AF: 0.235 AC: 496 AN: 2112

Alfa AF: 0.229 Hom.: 6892

Bravo AF: 0.211

Asia WGS AF: 0.387 AC: 1345 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.0
DANN	Benign	0.62
PhyloP100		1.1
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: rs1112269; hg19: chr1-210994395;