rs10410239

Variant names:

• chr19-13919876-T-C
• rs10410239
• NM_017721.5:c.1281T>C
• CC2D1A p.Gly427Gly

Variant summary

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

The NM_017721.5(CC2D1A):​c.1281T>C​(p.Gly427Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,611,382 control chromosomes in the GnomAD database, including 60,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (14790 hom., cov: 30)
  • Exomes 𝑓: 0.23 (45786 hom.)
• Consequence: CC2D1A NM_017721.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.31
• Publications: 16 publications found

Genes affected

CC2D1A (HGNC:30237): (coiled-coil and C2 domain containing 1A) This gene encodes a transcriptional repressor that binds to a conserved 14-bp 5'-repressor element and regulates expression of the 5-hydroxytryptamine (serotonin) receptor 1A gene in neuronal cells. The DNA binding and transcriptional repressor activities of the protein are inhibited by calcium. A mutation in this gene results in a nonsyndromic form of cognitive disability (MRT3). [provided by RefSeq, Jul 2017]

CC2D1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal recessive 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-13919876-T-C is Benign according to our data. Variant chr19-13919876-T-C is described in ClinVar as Benign. ClinVar VariationId is 128615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017721.5. 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
	CC2D1A	NM_017721.5	MANE Select	c.1281T>C	p.Gly427Gly	synonymous	Exon 12 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.1281T>C	p.Gly427Gly	synonymous	Exon 12 of 29	NP_001398067.1	Q6P1N0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	ENST00000318003.11	TSL:1 MANE Select	c.1281T>C	p.Gly427Gly	synonymous	Exon 12 of 29	ENSP00000313601.6	Q6P1N0-1
	CC2D1A	ENST00000589606.5	TSL:1	c.1281T>C	p.Gly427Gly	synonymous	Exon 12 of 29	ENSP00000467526.1	Q6P1N0-2
	CC2D1A	ENST00000586955.5	TSL:1	n.757+674T>C		intron	N/A	ENSP00000465376.1	K7EJY5

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56173 AN: 151536 Hom.: 14735 Cov.: 30

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.322

GnomAD2 exomes AF: 0.274 AC: 68267 AN: 249124 AF XY: 0.261

Gnomad AFR exome AF: 0.756

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.231 AC: 337799 AN: 1459732 Hom.: 45786 Cov.: 33 AF XY: 0.230 AC XY: 167054 AN XY: 726136

African (AFR) AF: 0.768 AC: 25664 AN: 33416

American (AMR) AF: 0.367 AC: 16397 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4786 AN: 26110

East Asian (EAS) AF: 0.280 AC: 11092 AN: 39662

South Asian (SAS) AF: 0.263 AC: 22667 AN: 86076

European-Finnish (FIN) AF: 0.173 AC: 9244 AN: 53368

Middle Eastern (MID) AF: 0.219 AC: 1140 AN: 5198

European-Non Finnish (NFE) AF: 0.208 AC: 231600 AN: 1111024

Other (OTH) AF: 0.253 AC: 15209 AN: 60218

GnomAD4 genome AF: 0.371 AC: 56292 AN: 151650 Hom.: 14790 Cov.: 30 AF XY: 0.367 AC XY: 27182 AN XY: 74118

African (AFR) AF: 0.746 AC: 30869 AN: 41380

American (AMR) AF: 0.361 AC: 5489 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 591 AN: 3462

East Asian (EAS) AF: 0.309 AC: 1582 AN: 5118

South Asian (SAS) AF: 0.287 AC: 1374 AN: 4794

European-Finnish (FIN) AF: 0.153 AC: 1607 AN: 10530

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13962 AN: 67874

Other (OTH) AF: 0.327 AC: 684 AN: 2092

Alfa AF: 0.278 Hom.: 4718

Bravo AF: 0.403

Asia WGS AF: 0.372 AC: 1290 AN: 3478

EpiCase AF: 0.205

EpiControl AF: 0.202

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.59
DANN	Benign	0.47
PhyloP100		-3.3
PromoterAI		-0.0040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10410239;

hg19: chr19-14030689;

COSMIC: COSV58784792;

COSMIC: COSV58784792;