rs2270694

Variant names:

• chr1-100484304-G-A
• rs2270694
• NM_003672.4:c.990G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003672.4(CDC14A):​c.990G>A​(p.Ser330Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,562,224 control chromosomes in the GnomAD database, including 12,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1129 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11175 hom.)
• Consequence: CDC14A NM_003672.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.23
• Publications: 11 publications found

Genes affected

CDC14A (HGNC:1718): (cell division cycle 14A) The protein encoded by this gene is a member of the dual specificity protein tyrosine phosphatase family. It is highly similar to Saccharomyces cerevisiae Cdc14, a protein tyrosine phosphatase involved in the exit of cell mitosis and initiation of DNA replication, suggesting a role in cell cycle control. This protein has been shown to interact with, and dephosphorylate tumor suppressor protein p53, and is thought to regulate the function of p53. Alternative splicing of this gene results in several transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

CDC14A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic deafness 105

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hearing impairment and infertile male syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 32

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000228086 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-100484304-G-A is Benign according to our data. Variant chr1-100484304-G-A is described in ClinVar as Benign. ClinVar VariationId is 508568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003672.4. 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
	CDC14A	NM_003672.4	MANE Select	c.990G>A	p.Ser330Ser	synonymous	Exon 11 of 16	NP_003663.2
	CDC14A	NM_033312.3		c.990G>A	p.Ser330Ser	synonymous	Exon 11 of 15	NP_201569.1	Q9UNH5-2
	CDC14A	NM_001319210.2		c.990G>A	p.Ser330Ser	synonymous	Exon 11 of 17	NP_001306139.1	Q9UNH5-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC14A	ENST00000336454.5	TSL:1 MANE Select	c.990G>A	p.Ser330Ser	synonymous	Exon 11 of 16	ENSP00000336739.3	Q9UNH5-1
	CDC14A	ENST00000361544.11	TSL:1	c.990G>A	p.Ser330Ser	synonymous	Exon 11 of 15	ENSP00000354916.6	Q9UNH5-2
	CDC14A	ENST00000370124.8	TSL:1	c.990G>A	p.Ser330Ser	synonymous	Exon 11 of 11	ENSP00000359142.3	Q9UNH5-3

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16967 AN: 151888 Hom.: 1128 Cov.: 32

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.0618

Gnomad SAS AF: 0.0936

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.117 AC: 24079 AN: 205850 AF XY: 0.119

Gnomad AFR exome AF: 0.0572

Gnomad AMR exome AF: 0.0868

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.0624

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.122 AC: 172533 AN: 1410220 Hom.: 11175 Cov.: 28 AF XY: 0.122 AC XY: 85737 AN XY: 701140

African (AFR) AF: 0.0575 AC: 1756 AN: 30528

American (AMR) AF: 0.0898 AC: 3140 AN: 34984

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5033 AN: 24294

East Asian (EAS) AF: 0.0617 AC: 2340 AN: 37904

South Asian (SAS) AF: 0.0896 AC: 7005 AN: 78196

European-Finnish (FIN) AF: 0.159 AC: 8279 AN: 52028

Middle Eastern (MID) AF: 0.130 AC: 726 AN: 5564

European-Non Finnish (NFE) AF: 0.126 AC: 137205 AN: 1088658

Other (OTH) AF: 0.121 AC: 7049 AN: 58064

GnomAD4 genome AF: 0.112 AC: 16972 AN: 152004 Hom.: 1129 Cov.: 32 AF XY: 0.113 AC XY: 8396 AN XY: 74280

African (AFR) AF: 0.0596 AC: 2472 AN: 41492

American (AMR) AF: 0.117 AC: 1782 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3472

East Asian (EAS) AF: 0.0618 AC: 320 AN: 5178

South Asian (SAS) AF: 0.0937 AC: 452 AN: 4824

European-Finnish (FIN) AF: 0.169 AC: 1778 AN: 10530

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8982 AN: 67938

Other (OTH) AF: 0.120 AC: 252 AN: 2108

Alfa AF: 0.127 Hom.: 2835

Bravo AF: 0.106

Asia WGS AF: 0.0700 AC: 242 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.68
DANN	Benign	0.84
PhyloP100		-1.2
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: rs2270694; hg19: chr1-100949860; COSMIC: COSV107404599;