chr1-111775862-A-G

Variant names:

• chr1-111775862-A-G
• rs12033257
• NM_001378969.1:c.*215T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378969.1(KCND3):​c.*215T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 303,530 control chromosomes in the GnomAD database, including 26,814 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (10804 hom., cov: 23)
  • Exomes 𝑓: 0.44 (16010 hom.)
• Consequence: KCND3 NM_001378969.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.591
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.*215T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000302127.5	NP_001365898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCND3	ENST00000302127.5	c.*215T>C		3_prime_UTR_variant	Exon 8 of 8	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.*215T>C		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.*215T>C		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000358711.1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 54918 AN: 137530 Hom.: 10799 Cov.: 23

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.416

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.438 AC: 72727 AN: 165916 Hom.: 16010 Cov.: 2 AF XY: 0.449 AC XY: 40244 AN XY: 89582

African (AFR) AF: 0.266 AC: 1410 AN: 5302

American (AMR) AF: 0.433 AC: 5771 AN: 13338

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1912 AN: 4284

East Asian (EAS) AF: 0.693 AC: 6076 AN: 8770

South Asian (SAS) AF: 0.518 AC: 15674 AN: 30268

European-Finnish (FIN) AF: 0.403 AC: 2980 AN: 7400

Middle Eastern (MID) AF: 0.376 AC: 219 AN: 582

European-Non Finnish (NFE) AF: 0.400 AC: 35079 AN: 87728

Other (OTH) AF: 0.437 AC: 3606 AN: 8244

GnomAD4 genome AF: 0.399 AC: 54944 AN: 137614 Hom.: 10804 Cov.: 23 AF XY: 0.414 AC XY: 27370 AN XY: 66150

African (AFR) AF: 0.292 AC: 10335 AN: 35450

American (AMR) AF: 0.485 AC: 6273 AN: 12936

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1528 AN: 3408

East Asian (EAS) AF: 0.707 AC: 3360 AN: 4754

South Asian (SAS) AF: 0.578 AC: 2545 AN: 4406

European-Finnish (FIN) AF: 0.483 AC: 4025 AN: 8338

Middle Eastern (MID) AF: 0.403 AC: 95 AN: 236

European-Non Finnish (NFE) AF: 0.392 AC: 25620 AN: 65330

Other (OTH) AF: 0.410 AC: 770 AN: 1876

Alfa AF: 0.373 Hom.: 6651

Bravo AF: 0.364

Asia WGS AF: 0.609 AC: 2112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.7
DANN	Benign	0.41
PhyloP100		-0.59
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: rs12033257; hg19: chr1-112318484;