chr7-150958354-G-T

Variant names:

• chr7-150958354-G-T
• rs41314417
• NM_000238.4:c.621C>A
• KCNH2 p.Ser207Arg

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000238.4(KCNH2):​c.621C>A​(p.Ser207Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S207S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25465858).

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>A	p.Ser207Arg	missense	Exon 4 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.333C>A	p.Ser111Arg	missense	Exon 2 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.621C>A	p.Ser207Arg	missense	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>A	p.Ser207Arg	missense	Exon 4 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.621C>A	p.Ser207Arg	missense	Exon 4 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.321C>A	p.Ser107Arg	missense	Exon 3 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1333464 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 658716

African (AFR) AF: 0.00 AC: 0 AN: 27322

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 4680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057388

Other (OTH) AF: 0.00 AC: 0 AN: 55176

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
CardioboostArm	Benign	0.00047
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.69	N
PhyloP100		0.65
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.33
Sift	Benign	0.17	T
Sift4G	Benign	0.28	T
Varity_R		0.056
gMVP		0.51
Mutation Taster		=83/17	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41314417; hg19: chr7-150655442;