rs139533994

Variant names:

• chr7-150958417-G-A
• rs139533994
• NM_000238.4:c.558C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150958417-G-A
• chr7-150958417-G-C
• chr7-150958417-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000238.4(KCNH2):​c.558C>T​(p.Gly186Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,439,032 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G186G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.452
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-150958417-G-A is Benign according to our data. Variant chr7-150958417-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 200214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.452 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00209 (317/151922) while in subpopulation AFR AF = 0.0072 (299/41504). AF 95% confidence interval is 0.00653. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 317 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. 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.558C>T	p.Gly186Gly	synonymous	Exon 4 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.270C>T	p.Gly90Gly	synonymous	Exon 2 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.558C>T	p.Gly186Gly	synonymous	Exon 4 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.558C>T	p.Gly186Gly	synonymous	Exon 4 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.558C>T	p.Gly186Gly	synonymous	Exon 4 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.258C>T	p.Gly86Gly	synonymous	Exon 3 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 151814 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00718

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000217 AC: 12 AN: 55250 AF XY: 0.0000923

Gnomad AFR exome AF: 0.00740

Gnomad AMR exome AF: 0.000576

Gnomad ASJ exome AF: 0.000427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000184 AC: 237 AN: 1287110 Hom.: 2 Cov.: 32 AF XY: 0.000159 AC XY: 101 AN XY: 633738

African (AFR) AF: 0.00652 AC: 166 AN: 25456

American (AMR) AF: 0.000465 AC: 9 AN: 19348

Ashkenazi Jewish (ASJ) AF: 0.0000949 AC: 2 AN: 21066

East Asian (EAS) AF: 0.00 AC: 0 AN: 27990

South Asian (SAS) AF: 0.00 AC: 0 AN: 66542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 0.0000280 AC: 29 AN: 1037232

Other (OTH) AF: 0.000584 AC: 31 AN: 53098

GnomAD4 genome AF: 0.00209 AC: 317 AN: 151922 Hom.: 2 Cov.: 33 AF XY: 0.00199 AC XY: 148 AN XY: 74282

African (AFR) AF: 0.00720 AC: 299 AN: 41504

American (AMR) AF: 0.000786 AC: 12 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67912

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000601 Hom.: 0

Bravo AF: 0.00238

Asia WGS AF: 0.000290 AC: 1 AN: 3458

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.4
DANN	Benign	0.91
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139533994; hg19: chr7-150655505;