rs2305777

Variant names:

• chr19-13927978-C-T
• rs2305777
• NM_017721.5:c.2402C>T
• CC2D1A p.Thr801Met

Your query was ambiguous. Multiple possible variants found:

• chr19-13927978-C-T
• chr19-13927978-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017721.5(CC2D1A):​c.2402C>T​(p.Thr801Met) variant causes a missense change. The variant allele was found at a frequency of 0.246 in 1,613,272 control chromosomes in the GnomAD database, including 52,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3521 hom., cov: 29)
  • Exomes 𝑓: 0.25 (49280 hom.)
• Consequence: CC2D1A NM_017721.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.16
• Publications: 32 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=0.0016435385).
• BP6: Variant 19-13927978-C-T is Benign according to our data. Variant chr19-13927978-C-T is described in ClinVar as Benign. ClinVar VariationId is 128619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 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.2402C>T	p.Thr801Met	missense	Exon 23 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.2402C>T	p.Thr801Met	missense	Exon 23 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.2402C>T	p.Thr801Met	missense	Exon 23 of 29	ENSP00000313601.6	Q6P1N0-1
	CC2D1A	ENST00000589606.5	TSL:1	c.2402C>T	p.Thr801Met	missense	Exon 23 of 29	ENSP00000467526.1	Q6P1N0-2
	CC2D1A	ENST00000586955.5	TSL:1	n.*669C>T		non_coding_transcript_exon	Exon 18 of 24	ENSP00000465376.1	K7EJY5

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28790 AN: 151692 Hom.: 3522 Cov.: 29

Gnomad AFR AF: 0.0495

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.0694

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.210 AC: 52471 AN: 249330 AF XY: 0.216

Gnomad AFR exome AF: 0.0434

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.0690

Gnomad FIN exome AF: 0.252

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.252 AC: 368728 AN: 1461462 Hom.: 49280 Cov.: 38 AF XY: 0.251 AC XY: 182399 AN XY: 727034

African (AFR) AF: 0.0376 AC: 1260 AN: 33478

American (AMR) AF: 0.155 AC: 6938 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6755 AN: 26134

East Asian (EAS) AF: 0.0718 AC: 2850 AN: 39698

South Asian (SAS) AF: 0.174 AC: 14976 AN: 86246

European-Finnish (FIN) AF: 0.260 AC: 13818 AN: 53202

Middle Eastern (MID) AF: 0.185 AC: 1067 AN: 5768

European-Non Finnish (NFE) AF: 0.276 AC: 307299 AN: 1111824

Other (OTH) AF: 0.228 AC: 13765 AN: 60390

GnomAD4 genome AF: 0.190 AC: 28783 AN: 151810 Hom.: 3521 Cov.: 29 AF XY: 0.186 AC XY: 13830 AN XY: 74164

African (AFR) AF: 0.0493 AC: 2046 AN: 41468

American (AMR) AF: 0.169 AC: 2573 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 948 AN: 3470

East Asian (EAS) AF: 0.0690 AC: 355 AN: 5148

South Asian (SAS) AF: 0.163 AC: 782 AN: 4810

European-Finnish (FIN) AF: 0.243 AC: 2547 AN: 10494

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18632 AN: 67886

Other (OTH) AF: 0.189 AC: 397 AN: 2102

Alfa AF: 0.240 Hom.: 19945

Bravo AF: 0.180

Asia WGS AF: 0.106 AC: 371 AN: 3478

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	Intellectual disability, autosomal recessive 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.077
Sift	Benign	0.15	T
Sift4G	Benign	0.13	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.37
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2305777;

hg19: chr19-14038791;

COSMIC: COSV54308018;

COSMIC: COSV54308018;