chr7-120742576-C-T

Variant names:

• chr7-120742576-C-T
• rs370190131
• NM_012281.3:c.1441C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_012281.3(KCND2):​c.1441C>T​(p.Leu481Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000497 in 1,613,502 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (3 hom.)
• Consequence: KCND2 NM_012281.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.54
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 7-120742576-C-T is Benign according to our data. Variant chr7-120742576-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 529729.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 68 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.1441C>T	p.Leu481Leu	synonymous	Exon 4 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.1441C>T	p.Leu481Leu	synonymous	Exon 4 of 6	ENSP00000333496.4	Q9NZV8
	KCND2	ENST00000425288.1	TSL:4	c.196C>T	p.Leu66Leu	synonymous	Exon 3 of 5	ENSP00000415463.1	H7C445
	KCND2	ENST00000473190.1	TSL:4	n.256C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000602 AC: 151 AN: 250862 AF XY: 0.000686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000609

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000502 AC: 734 AN: 1461276 Hom.: 3 Cov.: 30 AF XY: 0.000568 AC XY: 413 AN XY: 726938

African (AFR) AF: 0.0000598 AC: 2 AN: 33436

American (AMR) AF: 0.000626 AC: 28 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000985 AC: 85 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00521 AC: 30 AN: 5762

European-Non Finnish (NFE) AF: 0.000417 AC: 463 AN: 1111590

Other (OTH) AF: 0.000911 AC: 55 AN: 60342

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74424

African (AFR) AF: 0.000144 AC: 6 AN: 41542

American (AMR) AF: 0.000589 AC: 9 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68006

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000638 Hom.: 1

Bravo AF: 0.000465

EpiCase AF: 0.000655

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Early myoclonic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		4.5
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs370190131; hg19: chr7-120382630;