chr14-62708387-C-T

Variant names:

• chr14-62708387-C-T
• rs36004050
• NM_139318.5:c.2088G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_139318.5(KCNH5):​c.2088G>A​(p.Val696Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 1,613,142 control chromosomes in the GnomAD database, including 1,359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (118 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1241 hom.)
• Consequence: KCNH5 NM_139318.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.192
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-62708387-C-T is Benign according to our data. Variant chr14-62708387-C-T is described in ClinVar as Benign. ClinVar VariationId is 416125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.192 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0619 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.2088G>A	p.Val696Val	synonymous	Exon 11 of 11	NP_647479.2
	KCNH5	NM_172375.3		c.*55G>A		3_prime_UTR	Exon 10 of 10	NP_758963.1	Q8NCM2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.2088G>A	p.Val696Val	synonymous	Exon 11 of 11	ENSP00000321427.7	Q8NCM2-1
	KCNH5	ENST00000420622.6	TSL:1	c.*55G>A		3_prime_UTR	Exon 10 of 10	ENSP00000395439.2	Q8NCM2-2

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4650 AN: 152100 Hom.: 118 Cov.: 32

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0679

Gnomad FIN AF: 0.0733

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0347 AC: 8697 AN: 250560 AF XY: 0.0361

Gnomad AFR exome AF: 0.00517

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.0747

Gnomad NFE exome AF: 0.0396

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0371 AC: 54211 AN: 1460924 Hom.: 1241 Cov.: 34 AF XY: 0.0378 AC XY: 27460 AN XY: 726772

African (AFR) AF: 0.00448 AC: 150 AN: 33480

American (AMR) AF: 0.0122 AC: 544 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 168 AN: 26134

East Asian (EAS) AF: 0.00340 AC: 135 AN: 39694

South Asian (SAS) AF: 0.0609 AC: 5254 AN: 86252

European-Finnish (FIN) AF: 0.0716 AC: 3767 AN: 52638

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5758

European-Non Finnish (NFE) AF: 0.0380 AC: 42293 AN: 1111862

Other (OTH) AF: 0.0310 AC: 1874 AN: 60388

GnomAD4 genome AF: 0.0306 AC: 4655 AN: 152218 Hom.: 118 Cov.: 32 AF XY: 0.0325 AC XY: 2416 AN XY: 74440

African (AFR) AF: 0.00616 AC: 256 AN: 41546

American (AMR) AF: 0.0203 AC: 311 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5164

South Asian (SAS) AF: 0.0680 AC: 328 AN: 4826

European-Finnish (FIN) AF: 0.0733 AC: 777 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0415 AC: 2819 AN: 67994

Other (OTH) AF: 0.0313 AC: 66 AN: 2110

Alfa AF: 0.0345 Hom.: 413

Bravo AF: 0.0237

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.0327

EpiControl AF: 0.0328

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	KCNH5-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.2
DANN	Benign	0.69
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs36004050; hg19: chr14-63175105;