rs143529486

Variant names:

• chr19-13920624-C-T
• rs143529486
• NM_017721.5:c.1424C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_017721.5(CC2D1A):​c.1424C>T​(p.Ser475Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000286 in 1,611,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: CC2D1A NM_017721.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.13
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050014555).
• BP6: Variant 19-13920624-C-T is Benign according to our data. Variant chr19-13920624-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210593.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00147 (224/152120) while in subpopulation AFR AF = 0.00518 (215/41490). AF 95% confidence interval is 0.00461. There are 0 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1424C>T	p.Ser475Leu	missense	Exon 13 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.1424C>T	p.Ser475Leu	missense	Exon 13 of 29	NP_001398067.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	ENST00000318003.11	TSL:1 MANE Select	c.1424C>T	p.Ser475Leu	missense	Exon 13 of 29	ENSP00000313601.6
	CC2D1A	ENST00000589606.5	TSL:1	c.1424C>T	p.Ser475Leu	missense	Exon 13 of 29	ENSP00000467526.1
	CC2D1A	ENST00000586955.5	TSL:1	n.825C>T		non_coding_transcript_exon	Exon 8 of 24	ENSP00000465376.1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000347 AC: 84 AN: 241736 AF XY: 0.000198

Gnomad AFR exome AF: 0.00483

Gnomad AMR exome AF: 0.000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1459052 Hom.: 1 Cov.: 32 AF XY: 0.000141 AC XY: 102 AN XY: 725692

African (AFR) AF: 0.00551 AC: 184 AN: 33396

American (AMR) AF: 0.000316 AC: 14 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110692

Other (OTH) AF: 0.000514 AC: 31 AN: 60254

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00147 AC XY: 109 AN XY: 74354

African (AFR) AF: 0.00518 AC: 215 AN: 41490

American (AMR) AF: 0.000393 AC: 6 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000553 Hom.: 0

Bravo AF: 0.00183

ESP6500AA AF: 0.00340 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000340 AC: 41

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	CC2D1A-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (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	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.038
Sift	Benign	0.17	T
Sift4G	Benign	0.23	T
Polyphen		0.059	B
Vest4		0.22
MVP		0.37
MPC		0.21
ClinPred		0.018	T
GERP RS		5.3
Varity_R		0.032
gMVP		0.26
Mutation Taster		=88/12	polymorphism

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: rs143529486; hg19: chr19-14031437;