rs376443152

Positions:

• chr19-13929657-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017721.5(CC2D1A):​c.2707C>T​(p.Arg903Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,294,950 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 14)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: CC2D1A NM_017721.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.921

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08847353).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D1A	NM_017721.5	c.2707C>T	p.Arg903Trp	missense_variant	26/29	ENST00000318003.11	NP_060191.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D1A	ENST00000318003.11	c.2707C>T	p.Arg903Trp	missense_variant	26/29	1	NM_017721.5	ENSP00000313601.6

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 25 AN: 79622 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.000156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000781

Gnomad ASJ AF: 0.00135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000973

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000293

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000308 AC: 39 AN: 126696 Hom.: 1 AF XY: 0.000361 AC XY: 25 AN XY: 69180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000800

Gnomad FIN exome AF: 0.000203

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000907

GnomAD4 exome AF: 0.000177 AC: 215 AN: 1215294 Hom.: 3 Cov.: 33 AF XY: 0.000193 AC XY: 115 AN XY: 594620

Gnomad4 AFR exome AF: 0.0000367

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000425

Gnomad4 SAS exome AF: 0.000599

Gnomad4 FIN exome AF: 0.000146

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.000322

GnomAD4 genome AF: 0.000314 AC: 25 AN: 79656 Hom.: 0 Cov.: 14 AF XY: 0.000217 AC XY: 8 AN XY: 36926

Gnomad4 AFR AF: 0.000155

Gnomad4 AMR AF: 0.000779

Gnomad4 ASJ AF: 0.00135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000980

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000293

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000278 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000169 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2017

The p.R903W variant (also known as c.2707C>T), located in coding exon 26 of the CC2D1A gene, results from a C to T substitution at nucleotide position 2707. The arginine at codon 903 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 24, 2014

- -

Intellectual disability, autosomal recessive 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.48
MVP		0.39
MPC		0.64
ClinPred		0.064	T
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.096
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs376443152; hg19: chr19-14040470; COSMIC: COSV105031158; COSMIC: COSV105031158;