chrX-48966313-C-A

Variant names:

• chrX-48966313-C-A
• rs376253982
• NM_004979.6:c.1468-8G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5 BP4 BS2_Supporting

The NM_004979.6(KCND1):​c.1468-8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,174,893 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 10 hem., cov: 24)
  • Exomes 𝑓: 0.00027 (0 hom. 89 hem.)
• Consequence: KCND1 NM_004979.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001119
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.343
• Publications: 0 publications found

Genes affected

KCND1 (HGNC:6237): (potassium voltage-gated channel subfamily D member 1) This gene encodes a multipass membrane protein that comprises the pore subunit of the voltage-gated A-type potassium channel, which functions in the repolarization of membrane action potentials. Activity of voltage-gated potassium channels is important in a number of physiological processes, among them the regulation of neurotransmitter release, heart rate, insulin secretion, and smooth muscle contraction. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP5: Variant X-48966313-C-A is Pathogenic according to our data. Variant chrX-48966313-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 599560.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd4 at 10 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004979.6. 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
	KCND1	NM_004979.6	MANE Select	c.1468-8G>T		splice_region intron	N/A	NP_004970.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND1	ENST00000218176.4	TSL:1 MANE Select	c.1468-8G>T		splice_region intron	N/A	ENSP00000218176.3	Q9NSA2-1
	KCND1	ENST00000935975.1		c.1480-8G>T		splice_region intron	N/A	ENSP00000606034.1
	KCND1	ENST00000935976.1		c.1465-8G>T		splice_region intron	N/A	ENSP00000606035.1

Frequencies

GnomAD3 genomes AF: 0.000203 AC: 23 AN: 113451 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000790

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000337

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000202 AC: 25 AN: 123486 AF XY: 0.000123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000499

Gnomad NFE exome AF: 0.000367

Gnomad OTH exome AF: 0.000290

GnomAD4 exome AF: 0.000268 AC: 284 AN: 1061442 Hom.: 0 Cov.: 31 AF XY: 0.000258 AC XY: 89 AN XY: 344796

African (AFR) AF: 0.00 AC: 0 AN: 25869

American (AMR) AF: 0.0000357 AC: 1 AN: 28050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18651

East Asian (EAS) AF: 0.00 AC: 0 AN: 28709

South Asian (SAS) AF: 0.00 AC: 0 AN: 50430

European-Finnish (FIN) AF: 0.000707 AC: 27 AN: 38197

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3083

European-Non Finnish (NFE) AF: 0.000307 AC: 253 AN: 823732

Other (OTH) AF: 0.0000671 AC: 3 AN: 44721

GnomAD4 genome AF: 0.000203 AC: 23 AN: 113451 Hom.: 0 Cov.: 24 AF XY: 0.000281 AC XY: 10 AN XY: 35585

African (AFR) AF: 0.00 AC: 0 AN: 31292

American (AMR) AF: 0.00 AC: 0 AN: 10855

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2663

East Asian (EAS) AF: 0.00 AC: 0 AN: 3611

South Asian (SAS) AF: 0.00 AC: 0 AN: 2831

European-Finnish (FIN) AF: 0.000790 AC: 5 AN: 6331

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000337 AC: 18 AN: 53413

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.000356 Hom.: 2

Bravo AF: 0.000140

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Short stature (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.7
DANN	Benign	0.62
PhyloP100		-0.34
PromoterAI		0.086	Neutral
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0
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: rs376253982; hg19: chrX-48822720;