rs200121704

chr19-13918779-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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:6
• Conservation: PhyloP100: -0.177

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D1A	NM_017721.5	c.980C>T	p.Ser327Leu	missense_variant	9/29	ENST00000318003.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D1A	ENST00000318003.11	c.980C>T	p.Ser327Leu	missense_variant	9/29	1	NM_017721.5	P3

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

GnomAD3 exomes AF: 0.00920 AC: 2275 AN: 247258 Hom.: 19 AF XY: 0.0101 AC XY: 1351 AN XY: 134364

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 SAS exome AF: 0.0167

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

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00739

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.00222

Gnomad4 NFE exome AF: 0.00871

Gnomad4 OTH exome AF: 0.00909

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

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00929

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00960 Hom.: 5

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 15, 2016	- -

CC2D1A-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2019

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). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 17, 2015

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2016

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.62	N;.
REVEL	Benign	0.052
Sift	Benign	0.33	T;.
Sift4G	Benign	0.63	T;T
Polyphen		0.0	B;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

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