rs376336714

Variant names:

• chr19-13913595-C-T
• rs376336714
• NM_017721.5:c.705C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017721.5(CC2D1A):​c.705C>T​(p.Ala235Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,613,246 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: CC2D1A NM_017721.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.23
• Publications: 0 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), G2P, Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-13913595-C-T is Benign according to our data. Variant chr19-13913595-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 434596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.705C>T	p.Ala235Ala	synonymous	Exon 6 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.705C>T	p.Ala235Ala	synonymous	Exon 6 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.705C>T	p.Ala235Ala	synonymous	Exon 6 of 29	ENSP00000313601.6	Q6P1N0-1
	CC2D1A	ENST00000589606.5	TSL:1	c.705C>T	p.Ala235Ala	synonymous	Exon 6 of 29	ENSP00000467526.1	Q6P1N0-2
	CC2D1A	ENST00000586955.5	TSL:1	n.240C>T		non_coding_transcript_exon	Exon 2 of 24	ENSP00000465376.1	K7EJY5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000130 AC: 32 AN: 246836 AF XY: 0.000156

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000361 AC: 527 AN: 1460922 Hom.: 2 Cov.: 32 AF XY: 0.000351 AC XY: 255 AN XY: 726706

African (AFR) AF: 0.0000896 AC: 3 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000461 AC: 512 AN: 1111520

Other (OTH) AF: 0.000199 AC: 12 AN: 60350

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74480

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CC2D1A-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.6
DANN	Benign	0.48
PhyloP100		-1.2

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: rs376336714; hg19: chr19-14024408;