NM_000238.4:c.621C>T

Variant names:

• chr7-150958354-G-A
• rs41314417
• NM_000238.4:c.621C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000238.4(KCNH2):​c.621C>T​(p.Ser207Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,485,444 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.651
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 7-150958354-G-A is Benign according to our data. Variant chr7-150958354-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0027 (410/151980) while in subpopulation AFR AF = 0.00939 (390/41538). AF 95% confidence interval is 0.00862. There are 1 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 410 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.621C>T	p.Ser207Ser	synonymous	Exon 4 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.333C>T	p.Ser111Ser	synonymous	Exon 2 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.621C>T	p.Ser207Ser	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.621C>T	p.Ser207Ser	synonymous	Exon 4 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.621C>T	p.Ser207Ser	synonymous	Exon 4 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.321C>T	p.Ser107Ser	synonymous	Exon 3 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 151872 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000356 AC: 34 AN: 95418 AF XY: 0.000276

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000569

Gnomad ASJ exome AF: 0.00

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: 0.000247 AC: 330 AN: 1333464 Hom.: 2 Cov.: 32 AF XY: 0.000222 AC XY: 146 AN XY: 658716

African (AFR) AF: 0.00933 AC: 255 AN: 27322

American (AMR) AF: 0.000767 AC: 22 AN: 28670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23322

East Asian (EAS) AF: 0.00 AC: 0 AN: 29392

South Asian (SAS) AF: 0.00 AC: 0 AN: 74102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33412

Middle Eastern (MID) AF: 0.000641 AC: 3 AN: 4680

European-Non Finnish (NFE) AF: 0.0000142 AC: 15 AN: 1057388

Other (OTH) AF: 0.000634 AC: 35 AN: 55176

GnomAD4 genome AF: 0.00270 AC: 410 AN: 151980 Hom.: 1 Cov.: 33 AF XY: 0.00248 AC XY: 184 AN XY: 74316

African (AFR) AF: 0.00939 AC: 390 AN: 41538

American (AMR) AF: 0.000852 AC: 13 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67908

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00243 Hom.: 0

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	KCNH2-related disorder (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)
-	-	1	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41314417; hg19: chr7-150655442;