rs3762452

Variant names:

• chr1-211103486-C-T
• rs3762452
• NM_172362.3:c.310+10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172362.3(KCNH1):​c.310+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,523,160 control chromosomes in the GnomAD database, including 37,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3037 hom., cov: 33)
  • Exomes 𝑓: 0.22 (34341 hom.)
• Consequence: KCNH1 NM_172362.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.639
• 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: 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

ENSG00000283952 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-211103486-C-T is Benign according to our data. Variant chr1-211103486-C-T is described in ClinVar as Benign. ClinVar VariationId is 262807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 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.310+10G>A		intron	N/A	NP_758872.1	O95259-1
	KCNH1	NM_002238.4		c.310+10G>A		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.310+10G>A		intron	N/A	ENSP00000271751.4	O95259-1
	KCNH1	ENST00000639952.1	TSL:1	c.310+10G>A		intron	N/A	ENSP00000492697.1	O95259-2
	KCNH1	ENST00000640044.1	TSL:1	c.310+10G>A		intron	N/A	ENSP00000491434.1	A0A1W2PPA2

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29165 AN: 152056 Hom.: 3037 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.189 AC: 46772 AN: 247452 AF XY: 0.193

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.218 AC: 298787 AN: 1370986 Hom.: 34341 Cov.: 20 AF XY: 0.217 AC XY: 149011 AN XY: 686952

African (AFR) AF: 0.143 AC: 4522 AN: 31598

American (AMR) AF: 0.107 AC: 4703 AN: 43932

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6349 AN: 25346

East Asian (EAS) AF: 0.104 AC: 4071 AN: 39238

South Asian (SAS) AF: 0.158 AC: 13165 AN: 83498

European-Finnish (FIN) AF: 0.229 AC: 12161 AN: 53132

Middle Eastern (MID) AF: 0.227 AC: 1266 AN: 5576

European-Non Finnish (NFE) AF: 0.233 AC: 240428 AN: 1031442

Other (OTH) AF: 0.212 AC: 12122 AN: 57224

GnomAD4 genome AF: 0.192 AC: 29171 AN: 152174 Hom.: 3037 Cov.: 33 AF XY: 0.191 AC XY: 14229 AN XY: 74398

African (AFR) AF: 0.144 AC: 5976 AN: 41528

American (AMR) AF: 0.147 AC: 2243 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 870 AN: 3466

East Asian (EAS) AF: 0.112 AC: 580 AN: 5176

South Asian (SAS) AF: 0.150 AC: 722 AN: 4822

European-Finnish (FIN) AF: 0.241 AC: 2549 AN: 10594

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15631 AN: 67976

Other (OTH) AF: 0.194 AC: 410 AN: 2114

Alfa AF: 0.211 Hom.: 5065

Bravo AF: 0.183

Asia WGS AF: 0.119 AC: 411 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.8
DANN	Benign	0.73
PhyloP100		-0.64
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: rs3762452; hg19: chr1-211276828; COSMIC: COSV55082902; COSMIC: COSV55082902;