NM_172362.3:c.2112+8348C>T

Variant names:

• chr1-210767000-G-A
• rs1340128
• NM_172362.3:c.2112+8348C>T

Variant summary

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

The NM_172362.3(KCNH1):​c.2112+8348C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 152,120 control chromosomes in the GnomAD database, including 28,246 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 0.60 (28246 hom., cov: 33)
• Consequence: KCNH1 NM_172362.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.460
• Publications: 6 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172362.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH1	NM_172362.3	MANE Select	c.2112+8348C>T		intron	N/A	NP_758872.1
	KCNH1	NM_002238.4		c.2031+8348C>T		intron	N/A	NP_002229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH1	ENST00000271751.10	TSL:2 MANE Select	c.2112+8348C>T		intron	N/A	ENSP00000271751.4
	KCNH1	ENST00000639952.1	TSL:1	c.2031+8348C>T		intron	N/A	ENSP00000492697.1
	KCNH1	ENST00000640044.1	TSL:1	c.960+8348C>T		intron	N/A	ENSP00000491434.1

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91839 AN: 152002 Hom.: 28219 Cov.: 33

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.588

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

GnomAD4 genome AF: 0.604 AC: 91929 AN: 152120 Hom.: 28246 Cov.: 33 AF XY: 0.598 AC XY: 44473 AN XY: 74358

African (AFR) AF: 0.654 AC: 27159 AN: 41508

American (AMR) AF: 0.552 AC: 8433 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1876 AN: 3466

East Asian (EAS) AF: 0.291 AC: 1506 AN: 5170

South Asian (SAS) AF: 0.441 AC: 2127 AN: 4822

European-Finnish (FIN) AF: 0.643 AC: 6795 AN: 10560

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.622 AC: 42270 AN: 67994

Other (OTH) AF: 0.588 AC: 1244 AN: 2114

Alfa AF: 0.609 Hom.: 15314

Bravo AF: 0.598

Asia WGS AF: 0.425 AC: 1482 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.9
DANN	Benign	0.62
PhyloP100		0.46
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: rs1340128; hg19: chr1-210940342;