rs200121704

Variant names:

• chr19-13918779-C-T
• rs200121704
• NM_017721.5:c.980C>T

Variant summary

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

The NM_017721.5(CC2D1A):​c.980C>T​(p.Ser327Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00864 in 1,613,338 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (101 hom.)
• Consequence: CC2D1A NM_017721.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.177
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004861355).
• BP6: Variant 19-13918779-C-T is Benign according to our data. Variant chr19-13918779-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0069 (1051/152260) while in subpopulation SAS AF = 0.0139 (67/4826). AF 95% confidence interval is 0.0112. There are 4 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	NM_017721.5	MANE Select	c.980C>T	p.Ser327Leu	missense	Exon 9 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.980C>T	p.Ser327Leu	missense	Exon 9 of 29	NP_001398067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	ENST00000318003.11	TSL:1 MANE Select	c.980C>T	p.Ser327Leu	missense	Exon 9 of 29	ENSP00000313601.6
	CC2D1A	ENST00000589606.5	TSL:1	c.980C>T	p.Ser327Leu	missense	Exon 9 of 29	ENSP00000467526.1
	CC2D1A	ENST00000586955.5	TSL:1	n.515C>T		non_coding_transcript_exon	Exon 5 of 24	ENSP00000465376.1

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1051 AN: 152142 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00929

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00920 AC: 2275 AN: 247258 AF XY: 0.0101

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00732

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.00228

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00883 AC: 12895 AN: 1461078 Hom.: 101 Cov.: 33 AF XY: 0.00926 AC XY: 6732 AN XY: 726804

African (AFR) AF: 0.00114 AC: 38 AN: 33474

American (AMR) AF: 0.00739 AC: 330 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 579 AN: 26100

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0173 AC: 1494 AN: 86132

European-Finnish (FIN) AF: 0.00222 AC: 118 AN: 53236

Middle Eastern (MID) AF: 0.0180 AC: 103 AN: 5730

European-Non Finnish (NFE) AF: 0.00871 AC: 9679 AN: 1111700

Other (OTH) AF: 0.00909 AC: 549 AN: 60366

GnomAD4 genome AF: 0.00690 AC: 1051 AN: 152260 Hom.: 4 Cov.: 32 AF XY: 0.00712 AC XY: 530 AN XY: 74444

African (AFR) AF: 0.00156 AC: 65 AN: 41546

American (AMR) AF: 0.0104 AC: 159 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4826

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00929 AC: 632 AN: 68000

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00897 Hom.: 7

Bravo AF: 0.00670

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.000498 AC: 2

ESP6500EA AF: 0.00793 AC: 66

ExAC AF: 0.00928 AC: 1122

Asia WGS AF: 0.00751 AC: 28 AN: 3476

EpiCase AF: 0.0104

EpiControl AF: 0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Nov 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CC2D1A: BP4, BS1, BS2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 17, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CC2D1A-related disorder Benign:1

May 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Inborn genetic diseases Benign:1

May 24, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Intellectual disability, autosomal recessive 3 Benign:1

Jul 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.0
DANN	Benign	0.86
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-0.18
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.052
Sift	Benign	0.33	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.072
MVP		0.20
MPC		0.19
ClinPred		0.0041	T
GERP RS		1.5
Varity_R		0.025
gMVP		0.12
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200121704; hg19: chr19-14029592; COSMIC: COSV58785137; COSMIC: COSV58785137;