chr1-210683262-T-G

Variant names:

• chr1-210683262-T-G
• rs34689382
• NM_172362.3:c.*19A>C

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.*19A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,604,628 control chromosomes in the GnomAD database, including 3,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (265 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3504 hom.)
• Consequence: KCNH1 NM_172362.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.493
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-210683262-T-G is Benign according to our data. Variant chr1-210683262-T-G is described in ClinVar as Benign. ClinVar VariationId is 1277290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0722 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.*19A>C		3_prime_UTR	Exon 11 of 11	NP_758872.1	O95259-1
	KCNH1	NM_002238.4		c.*19A>C		3_prime_UTR	Exon 11 of 11	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.*19A>C		3_prime_UTR	Exon 11 of 11	ENSP00000271751.4	O95259-1
	KCNH1	ENST00000639952.1	TSL:1	c.*19A>C		3_prime_UTR	Exon 11 of 11	ENSP00000492697.1	O95259-2
	KCNH1	ENST00000865058.1		c.*19A>C		3_prime_UTR	Exon 10 of 10	ENSP00000535117.1

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 7357 AN: 151752 Hom.: 265 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0583

Gnomad ASJ AF: 0.0497

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0489

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.0619

GnomAD2 exomes AF: 0.0561 AC: 13239 AN: 236192 AF XY: 0.0586

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.0437

Gnomad ASJ exome AF: 0.0581

Gnomad EAS exome AF: 0.000393

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0773

Gnomad OTH exome AF: 0.0727

GnomAD4 exome AF: 0.0662 AC: 96153 AN: 1452758 Hom.: 3504 Cov.: 36 AF XY: 0.0661 AC XY: 47697 AN XY: 722020

African (AFR) AF: 0.0111 AC: 365 AN: 32936

American (AMR) AF: 0.0444 AC: 1941 AN: 43748

Ashkenazi Jewish (ASJ) AF: 0.0509 AC: 1313 AN: 25808

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39614

South Asian (SAS) AF: 0.0500 AC: 4265 AN: 85354

European-Finnish (FIN) AF: 0.0358 AC: 1875 AN: 52310

Middle Eastern (MID) AF: 0.0918 AC: 526 AN: 5728

European-Non Finnish (NFE) AF: 0.0742 AC: 82211 AN: 1107308

Other (OTH) AF: 0.0609 AC: 3650 AN: 59952

GnomAD4 genome AF: 0.0484 AC: 7358 AN: 151870 Hom.: 265 Cov.: 32 AF XY: 0.0480 AC XY: 3564 AN XY: 74210

African (AFR) AF: 0.0127 AC: 526 AN: 41420

American (AMR) AF: 0.0582 AC: 887 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0497 AC: 172 AN: 3464

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5148

South Asian (SAS) AF: 0.0489 AC: 234 AN: 4786

European-Finnish (FIN) AF: 0.0343 AC: 362 AN: 10566

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0739 AC: 5018 AN: 67930

Other (OTH) AF: 0.0613 AC: 129 AN: 2106

Alfa AF: 0.0668 Hom.: 156

Bravo AF: 0.0488

Asia WGS AF: 0.0340 AC: 117 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.55
DANN	Benign	0.64
PhyloP100		-0.49
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: rs34689382; hg19: chr1-210856604;