14-62707898-T-C

Variant names:

• chr14-62707898-T-C
• rs7161127
• NM_139318.5:c.2577A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_139318.5(KCNH5):​c.2577A>G​(p.Arg859Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,614,112 control chromosomes in the GnomAD database, including 777,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (67074 hom., cov: 31)
  • Exomes 𝑓: 0.99 (710712 hom.)
• Consequence: KCNH5 NM_139318.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.932
• Publications: 15 publications found

Genes affected

KCNH5 (HGNC:6254): (potassium voltage-gated channel subfamily H member 5) This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

KCNH5 Gene-Disease associations (from GenCC):

• infantile-onset epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 112

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 14-62707898-T-C is Benign according to our data. Variant chr14-62707898-T-C is described in ClinVar as Benign. ClinVar VariationId is 1166142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.932 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139318.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.2577A>G	p.Arg859Arg	synonymous	Exon 11 of 11	NP_647479.2
	KCNH5	NM_172375.3		c.*544A>G		3_prime_UTR	Exon 10 of 10	NP_758963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.2577A>G	p.Arg859Arg	synonymous	Exon 11 of 11	ENSP00000321427.7
	KCNH5	ENST00000420622.6	TSL:1	c.*544A>G		3_prime_UTR	Exon 10 of 10	ENSP00000395439.2

Frequencies

GnomAD3 genomes AF: 0.935 AC: 142202 AN: 152104 Hom.: 67039 Cov.: 31

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.963

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.938

GnomAD2 exomes AF: 0.976 AC: 245352 AN: 251490 AF XY: 0.979

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.980

Gnomad ASJ exome AF: 0.972

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.996

Gnomad NFE exome AF: 0.991

Gnomad OTH exome AF: 0.978

GnomAD4 exome AF: 0.986 AC: 1440752 AN: 1461890 Hom.: 710712 Cov.: 69 AF XY: 0.986 AC XY: 716977 AN XY: 727244

African (AFR) AF: 0.787 AC: 26344 AN: 33480

American (AMR) AF: 0.979 AC: 43793 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.972 AC: 25399 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 0.981 AC: 84624 AN: 86256

European-Finnish (FIN) AF: 0.997 AC: 53236 AN: 53420

Middle Eastern (MID) AF: 0.961 AC: 5544 AN: 5768

European-Non Finnish (NFE) AF: 0.992 AC: 1103125 AN: 1112010

Other (OTH) AF: 0.977 AC: 58989 AN: 60396

GnomAD4 genome AF: 0.935 AC: 142289 AN: 152222 Hom.: 67074 Cov.: 31 AF XY: 0.936 AC XY: 69680 AN XY: 74428

African (AFR) AF: 0.797 AC: 33089 AN: 41494

American (AMR) AF: 0.964 AC: 14742 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 3371 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5158 AN: 5162

South Asian (SAS) AF: 0.982 AC: 4737 AN: 4826

European-Finnish (FIN) AF: 0.996 AC: 10579 AN: 10618

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.991 AC: 67434 AN: 68028

Other (OTH) AF: 0.940 AC: 1988 AN: 2116

Alfa AF: 0.968 Hom.: 104134

Bravo AF: 0.927

Asia WGS AF: 0.977 AC: 3394 AN: 3478

EpiCase AF: 0.989

EpiControl AF: 0.988

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.9
DANN	Benign	0.47
PhyloP100		0.93
Mutation Taster		=98/2	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: rs7161127; hg19: chr14-63174616; COSMIC: COSV59774966; COSMIC: COSV59774966;