chr14-62950126-T-C

Variant names:

• chr14-62950126-T-C
• rs79489451
• NM_139318.5:c.1369+7A>G

Variant summary

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

The NM_139318.5(KCNH5):​c.1369+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,612,270 control chromosomes in the GnomAD database, including 21 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00076 (10 hom.)
• Consequence: KCNH5 NM_139318.5 splice_region, intron
• Scores: Splicing: ADA: 0.01885
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.66
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 14-62950126-T-C is Benign according to our data. Variant chr14-62950126-T-C is described in ClinVar as Benign. ClinVar VariationId is 416118.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 = 0.00762 (1160/152242) while in subpopulation AFR AF = 0.0265 (1102/41548). AF 95% confidence interval is 0.0252. There are 11 homozygotes in GnomAd4. There are 543 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1160 AD gene.

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.1369+7A>G		splice_region intron	N/A	NP_647479.2
	KCNH5	NM_172375.3		c.1369+7A>G		splice_region intron	N/A	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.1369+7A>G		splice_region intron	N/A	ENSP00000321427.7	Q8NCM2-1
	KCNH5	ENST00000420622.6	TSL:1	c.1369+7A>G		splice_region intron	N/A	ENSP00000395439.2	Q8NCM2-2
	KCNH5	ENST00000394964.3	TSL:1	n.1541A>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.00761 AC: 1158 AN: 152124 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00205 AC: 511 AN: 249754 AF XY: 0.00169

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000756 AC: 1104 AN: 1460028 Hom.: 10 Cov.: 30 AF XY: 0.000651 AC XY: 473 AN XY: 726330

African (AFR) AF: 0.0266 AC: 888 AN: 33380

American (AMR) AF: 0.00144 AC: 64 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5758

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111114

Other (OTH) AF: 0.00162 AC: 98 AN: 60316

GnomAD4 genome AF: 0.00762 AC: 1160 AN: 152242 Hom.: 11 Cov.: 31 AF XY: 0.00730 AC XY: 543 AN XY: 74432

African (AFR) AF: 0.0265 AC: 1102 AN: 41548

American (AMR) AF: 0.00255 AC: 39 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00669 Hom.: 6

Bravo AF: 0.00869

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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 specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Uncertain	0.99
PhyloP100		2.7
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.019
dbscSNV1_RF	Benign	0.058
SpliceAI score (max)		0.080		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: rs79489451; hg19: chr14-63416844;