7-120745785-C-T

Variant names:

• chr7-120745785-C-T
• rs145422660
• NM_012281.3:c.1473C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4 BP6_Very_Strong BP7 BS2

The NM_012281.3(KCND2):​c.1473C>T​(p.His491His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,584 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: KCND2 NM_012281.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.15
• Publications: 1 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 (REVEL=0.266).
• BP6: Variant 7-120745785-C-T is Benign according to our data. Variant chr7-120745785-C-T is described in ClinVar as Benign. ClinVar VariationId is 460199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BS2: High AC in GnomAd4 at 181 AD gene.

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.1473C>T	p.His491His	synonymous	Exon 5 of 6	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.1473C>T	p.His491His	synonymous	Exon 5 of 6	ENSP00000333496.4	Q9NZV8
	KCND2	ENST00000425288.1	TSL:4	c.228C>T	p.His76His	synonymous	Exon 4 of 5	ENSP00000415463.1	H7C445
	KCND2	ENST00000473190.1	TSL:4	n.288C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000383 AC: 96 AN: 250540 AF XY: 0.000303

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1461308 Hom.: 1 Cov.: 32 AF XY: 0.000113 AC XY: 82 AN XY: 726962

African (AFR) AF: 0.00454 AC: 152 AN: 33444

American (AMR) AF: 0.000224 AC: 10 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111664

Other (OTH) AF: 0.000265 AC: 16 AN: 60358

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74444

African (AFR) AF: 0.00419 AC: 174 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000629 Hom.: 0

Bravo AF: 0.00127

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Early myoclonic encephalopathy (1)
-	-	1	KCND2-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.34
DANN	Benign	0.84
PhyloP100		-1.1
Mutation Taster		=96/4	polymorphism

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: rs145422660; hg19: chr7-120385839;