1-210794655-A-G

Variant names:

• chr1-210794655-A-G
• rs1934613
• NM_172362.3:c.1915+2853T>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.1915+2853T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,162 control chromosomes in the GnomAD database, including 2,557 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 (2557 hom., cov: 32)
• Consequence: KCNH1 NM_172362.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.502
• 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: Illumina, ClinGen
• Temple-Baraitser syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH1	NM_172362.3	MANE Select	c.1915+2853T>C		intron	N/A	NP_758872.1	O95259-1
	KCNH1	NM_002238.4		c.1834+2853T>C		intron	N/A	NP_002229.1	O95259-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH1	ENST00000271751.10	TSL:2 MANE Select	c.1915+2853T>C		intron	N/A	ENSP00000271751.4	O95259-1
	KCNH1	ENST00000639952.1	TSL:1	c.1834+2853T>C		intron	N/A	ENSP00000492697.1	O95259-2
	KCNH1	ENST00000640044.1	TSL:1	c.763+2853T>C		intron	N/A	ENSP00000491434.1	A0A1W2PPA2

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26816 AN: 152044 Hom.: 2549 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.0314

Gnomad SAS AF: 0.0765

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.163

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

GnomAD4 genome AF: 0.176 AC: 26854 AN: 152162 Hom.: 2557 Cov.: 32 AF XY: 0.172 AC XY: 12804 AN XY: 74428

African (AFR) AF: 0.247 AC: 10235 AN: 41480

American (AMR) AF: 0.162 AC: 2475 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 545 AN: 3466

East Asian (EAS) AF: 0.0311 AC: 161 AN: 5176

South Asian (SAS) AF: 0.0778 AC: 375 AN: 4822

European-Finnish (FIN) AF: 0.161 AC: 1703 AN: 10606

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10928 AN: 67996

Other (OTH) AF: 0.163 AC: 344 AN: 2116

Alfa AF: 0.164 Hom.: 1756

Bravo AF: 0.178

Asia WGS AF: 0.0730 AC: 259 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		0.50
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: rs1934613; hg19: chr1-210967997;