rs201244697

chr7-120742502-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_012281.3(KCND2):c.1375-8G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000869 in 1,611,756 control chromosomes in the GnomAD database, including 2 homozygotes. 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 benign (★).

• Frequency:
  • Genomes: 𝑓 0.00087 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: KCND2 NM_012281.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002643
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.925

Genes affected

KCND2 (HGNC:6238): (potassium voltage-gated channel subfamily D member 2) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member mediates a rapidly inactivating, A-type outward potassium current which is not under the control of the N terminus as it is in Shaker channels. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 7-120742502-G-T is Benign according to our data. Variant chr7-120742502-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 460198.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCND2	NM_012281.3	c.1375-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000331113.9
KCND2	XM_047420346.1	c.1375-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCND2	ENST00000331113.9	c.1375-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_012281.3	P1
KCND2	ENST00000425288.1	c.132-8G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		4
KCND2	ENST00000473190.1	n.182G>T		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 132 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000661 AC: 166 AN: 251042 Hom.: 0 AF XY: 0.000708 AC XY: 96 AN XY: 135662

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000855

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000869 AC: 1268 AN: 1459606 Hom.: 1 Cov.: 30 AF XY: 0.000811 AC XY: 589 AN XY: 726264

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000713

GnomAD4 genome AF: 0.000868 AC: 132 AN: 152150 Hom.: 1 Cov.: 32 AF XY: 0.000942 AC XY: 70 AN XY: 74306

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.000914

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early myoclonic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	12
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
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

Publications

LitVar

Other links and lift over

dbSNP: rs201244697; hg19: chr7-120382556;