rs192358667

Variant names:

• chr19-13912529-C-A
• rs192358667
• NM_017721.5:c.314C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-13912529-C-A
• chr19-13912529-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017721.5(CC2D1A):​c.314C>A​(p.Ala105Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A105V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CC2D1A NM_017721.5 missense, splice_region
• Scores: Splicing: ADA: 0.9704
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D1A	NM_017721.5	c.314C>A	p.Ala105Glu	missense_variant, splice_region_variant	Exon 4 of 29	ENST00000318003.11	NP_060191.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D1A	ENST00000318003.11	c.314C>A	p.Ala105Glu	missense_variant, splice_region_variant	Exon 4 of 29	1	NM_017721.5	ENSP00000313601.6
CC2D1A	ENST00000589606.5	c.314C>A	p.Ala105Glu	missense_variant, splice_region_variant	Exon 4 of 29	1		ENSP00000467526.1
CC2D1A	ENST00000680439.1	n.472C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 7
CC2D1A	ENST00000585896.5	n.436-639C>A		intron_variant	Intron 2 of 9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.9	M;M
PhyloP100		3.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.17
Sift	Benign	0.068	T;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.51
MutPred		0.18		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.67
MPC		0.88
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.58
gMVP		0.50
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.020		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: rs192358667; hg19: chr19-14023342;