1-111775852-A-G

Variant names:

• chr1-111775852-A-G
• rs72548736
• NM_001378969.1:c.*225T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378969.1(KCND3):​c.*225T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (6 hom., cov: 16)
  • Exomes 𝑓: 0.0096 (4 hom.)
• Consequence: KCND3 NM_001378969.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.460
• Publications: 0 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]

DDX20 (HGNC:2743): (DEAD-box helicase 20) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which has an ATPase activity and is a component of the survival of motor neurons (SMN) complex. This protein interacts directly with SMN, the spinal muscular atrophy gene product, and may play a catalytic role in the function of the SMN complex on RNPs. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-111775852-A-G is Benign according to our data. Variant chr1-111775852-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1197975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0143 (940/65654) while in subpopulation NFE AF = 0.0174 (629/36054). AF 95% confidence interval is 0.0163. There are 6 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check.
• BS2: High AC in GnomAd4 at 940 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCND3	NM_001378969.1	c.*225T>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.*225T>C		3_prime_UTR_variant	Exon 8 of 8	5	NM_001378969.1	ENSP00000306923.4
KCND3	ENST00000315987.6	c.*225T>C		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000319591.2
KCND3	ENST00000369697.5	c.*225T>C		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000358711.1
DDX20	ENST00000680627.1	c.*1285A>G		downstream_gene_variant				ENSP00000505758.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 940 AN: 65630 Hom.: 6 Cov.: 16

Gnomad AFR AF: 0.00315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00641

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00406

Gnomad FIN AF: 0.0798

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.00937

GnomAD4 exome AF: 0.00959 AC: 406 AN: 42322 Hom.: 4 Cov.: 0 AF XY: 0.00842 AC XY: 197 AN XY: 23406

African (AFR) AF: 0.00238 AC: 3 AN: 1260

American (AMR) AF: 0.00428 AC: 18 AN: 4210

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 5 AN: 1084

East Asian (EAS) AF: 0.000380 AC: 1 AN: 2632

South Asian (SAS) AF: 0.00215 AC: 18 AN: 8386

European-Finnish (FIN) AF: 0.0268 AC: 48 AN: 1788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.0140 AC: 292 AN: 20840

Other (OTH) AF: 0.0105 AC: 21 AN: 2000

GnomAD4 genome AF: 0.0143 AC: 940 AN: 65654 Hom.: 6 Cov.: 16 AF XY: 0.0155 AC XY: 482 AN XY: 31014

African (AFR) AF: 0.00315 AC: 50 AN: 15892

American (AMR) AF: 0.0103 AC: 44 AN: 4270

Ashkenazi Jewish (ASJ) AF: 0.00641 AC: 12 AN: 1872

East Asian (EAS) AF: 0.00 AC: 0 AN: 1992

South Asian (SAS) AF: 0.00406 AC: 7 AN: 1726

European-Finnish (FIN) AF: 0.0798 AC: 190 AN: 2382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 54

European-Non Finnish (NFE) AF: 0.0174 AC: 629 AN: 36054

Other (OTH) AF: 0.00930 AC: 8 AN: 860

Alfa AF: 0.00838 Hom.: 2

Bravo AF: 0.00481

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.47
CADD	Benign	15
DANN	Benign	0.64
PhyloP100		0.46
Mutation Taster		=100/0	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: rs72548736; hg19: chr1-112318474;