rs56282717

Variant names:

• chr7-150960007-G-A
• rs56282717
• NM_000238.4:c.308-271C>T

Variant summary

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

The NM_001406753.1(KCNH2):​c.-252C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,174 control chromosomes in the GnomAD database, including 2,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.16 (2649 hom., cov: 32)
• Consequence: KCNH2 NM_001406753.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.725
• Publications: 6 publications found

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-150960007-G-A is Benign according to our data. Variant chr7-150960007-G-A is described in ClinVar as Benign. ClinVar VariationId is 668720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406753.1. 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
	KCNH2	NM_000238.4	MANE Select	c.308-271C>T		intron	N/A	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.-252C>T		5_prime_UTR	Exon 1 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_001406756.1		c.-252C>T		5_prime_UTR	Exon 1 of 7	NP_001393685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.308-271C>T		intron	N/A	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.308-271C>T		intron	N/A	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.8-271C>T		intron	N/A	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24650 AN: 152054 Hom.: 2645 Cov.: 32

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.0388

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.181

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

GnomAD4 genome AF: 0.162 AC: 24647 AN: 152174 Hom.: 2649 Cov.: 32 AF XY: 0.159 AC XY: 11824 AN XY: 74382

African (AFR) AF: 0.0413 AC: 1716 AN: 41536

American (AMR) AF: 0.162 AC: 2472 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 643 AN: 3468

East Asian (EAS) AF: 0.0389 AC: 201 AN: 5168

South Asian (SAS) AF: 0.206 AC: 996 AN: 4830

European-Finnish (FIN) AF: 0.161 AC: 1699 AN: 10576

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16249 AN: 68000

Other (OTH) AF: 0.180 AC: 381 AN: 2112

Alfa AF: 0.202 Hom.: 4589

Bravo AF: 0.153

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

ClinVar submissions

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	-0.80
CADD	Benign	0.25
DANN	Benign	0.62
PhyloP100		-0.72
Mutation Taster		=300/0	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: rs56282717; hg19: chr7-150657095;