rs12673992

Variant names:

• chr7-120732769-A-G
• rs12673992
• NM_012281.3:c.1116-134A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012281.3(KCND2):​c.1116-134A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 657,464 control chromosomes in the GnomAD database, including 37,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (14667 hom., cov: 32)
  • Exomes 𝑓: 0.29 (23303 hom.)
• Consequence: KCND2 NM_012281.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.325
• Publications: 5 publications found

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]

KCND2 Gene-Disease associations (from GenCC):

• KCND2-related neurodevelopmental disorder with or without seizures

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-120732769-A-G is Benign according to our data. Variant chr7-120732769-A-G is described in ClinVar as Benign. ClinVar VariationId is 1241406.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012281.3. 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
	KCND2	NM_012281.3	MANE Select	c.1116-134A>G		intron	N/A	NP_036413.1	Q9NZV8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND2	ENST00000331113.9	TSL:1 MANE Select	c.1116-134A>G		intron	N/A	ENSP00000333496.4	Q9NZV8

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59686 AN: 151880 Hom.: 14611 Cov.: 32

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.351

GnomAD4 exome AF: 0.286 AC: 144433 AN: 505466 Hom.: 23303 AF XY: 0.279 AC XY: 75568 AN XY: 270986

African (AFR) AF: 0.690 AC: 9164 AN: 13288

American (AMR) AF: 0.386 AC: 8143 AN: 21094

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 3235 AN: 16066

East Asian (EAS) AF: 0.506 AC: 15716 AN: 31080

South Asian (SAS) AF: 0.244 AC: 11344 AN: 46460

European-Finnish (FIN) AF: 0.360 AC: 12886 AN: 35836

Middle Eastern (MID) AF: 0.249 AC: 537 AN: 2156

European-Non Finnish (NFE) AF: 0.241 AC: 75138 AN: 311520

Other (OTH) AF: 0.296 AC: 8270 AN: 27966

GnomAD4 genome AF: 0.394 AC: 59816 AN: 151998 Hom.: 14667 Cov.: 32 AF XY: 0.395 AC XY: 29315 AN XY: 74290

African (AFR) AF: 0.690 AC: 28616 AN: 41444

American (AMR) AF: 0.346 AC: 5279 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 747 AN: 3472

East Asian (EAS) AF: 0.468 AC: 2419 AN: 5172

South Asian (SAS) AF: 0.249 AC: 1196 AN: 4812

European-Finnish (FIN) AF: 0.374 AC: 3946 AN: 10550

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16436 AN: 67974

Other (OTH) AF: 0.359 AC: 756 AN: 2106

Alfa AF: 0.281 Hom.: 5215

Bravo AF: 0.410

Asia WGS AF: 0.393 AC: 1362 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.64
PhyloP100		-0.33
Mutation Taster		=100/0	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: rs12673992; hg19: chr7-120372823; COSMIC: COSV58606276;