1-111780417-ATTT-ATTTT

Variant names:

• chr1-111780417-A-AT
• rs72548727
• NM_001378969.1:c.1372-104dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001378969.1(KCND3):​c.1372-104dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,170,170 control chromosomes in the GnomAD database, including 423 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (81 hom., cov: 32)
  • Exomes 𝑓: 0.023 (342 hom.)
• Consequence: KCND3 NM_001378969.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.72
• Publications: 2 publications found

Genes affected

KCND3 (HGNC:6239): (potassium voltage-gated channel subfamily D member 3) 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 includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

KCND3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• spinocerebellar ataxia type 19/22

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• Brugada syndrome 9

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-111780417-A-AT is Benign according to our data. Variant chr1-111780417-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 678725.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0613 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378969.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	NM_001378969.1	MANE Select	c.1372-104dupA		intron	N/A	NP_001365898.1
	KCND3	NM_004980.5		c.1372-104dupA		intron	N/A	NP_004971.2
	KCND3	NM_001378970.1		c.1372-104dupA		intron	N/A	NP_001365899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCND3	ENST00000302127.5	TSL:5 MANE Select	c.1372-104_1372-103insA		intron	N/A	ENSP00000306923.4
	KCND3	ENST00000315987.6	TSL:1	c.1372-104_1372-103insA		intron	N/A	ENSP00000319591.2
	KCND3	ENST00000369697.5	TSL:1	c.1372-104_1372-103insA		intron	N/A	ENSP00000358711.1

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4431 AN: 151618 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0323

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.0557

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.0666

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0279

GnomAD4 exome AF: 0.0225 AC: 22937 AN: 1018434 Hom.: 342 AF XY: 0.0233 AC XY: 12094 AN XY: 517948

African (AFR) AF: 0.0295 AC: 698 AN: 23638

American (AMR) AF: 0.0519 AC: 1768 AN: 34072

Ashkenazi Jewish (ASJ) AF: 0.00902 AC: 204 AN: 22616

East Asian (EAS) AF: 0.0610 AC: 2060 AN: 33744

South Asian (SAS) AF: 0.0436 AC: 3084 AN: 70722

European-Finnish (FIN) AF: 0.0174 AC: 840 AN: 48144

Middle Eastern (MID) AF: 0.0209 AC: 91 AN: 4350

European-Non Finnish (NFE) AF: 0.0176 AC: 12970 AN: 736262

Other (OTH) AF: 0.0272 AC: 1222 AN: 44886

GnomAD4 genome AF: 0.0292 AC: 4434 AN: 151736 Hom.: 81 Cov.: 32 AF XY: 0.0320 AC XY: 2370 AN XY: 74152

African (AFR) AF: 0.0322 AC: 1335 AN: 41398

American (AMR) AF: 0.0555 AC: 846 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3462

East Asian (EAS) AF: 0.0672 AC: 346 AN: 5152

South Asian (SAS) AF: 0.0446 AC: 214 AN: 4798

European-Finnish (FIN) AF: 0.0221 AC: 233 AN: 10526

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0195 AC: 1326 AN: 67864

Other (OTH) AF: 0.0276 AC: 58 AN: 2100

Alfa AF: 0.00523 Hom.: 2

Bravo AF: 0.0303

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.7
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: rs72548727; hg19: chr1-112323039;