19-13906478-A-G

Variant names:

• chr19-13906478-A-G
• rs748655557
• NM_017721.5:c.37A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017721.5(CC2D1A):​c.37A>G​(p.Arg13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,359,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R13R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CC2D1A NM_017721.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• 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]

BRME1 (HGNC:28153): (break repair meiotic recombinase recruitment factor 1) Predicted to be involved in meiosis I and spermatogenesis. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2864137).

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.37A>G	p.Arg13Gly	missense	Exon 1 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.37A>G	p.Arg13Gly	missense	Exon 1 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.37A>G	p.Arg13Gly	missense	Exon 1 of 29	ENSP00000313601.6	Q6P1N0-1
	CC2D1A	ENST00000589606.5	TSL:1	c.37A>G	p.Arg13Gly	missense	Exon 1 of 29	ENSP00000467526.1	Q6P1N0-2
	CC2D1A	ENST00000870936.1		c.37A>G	p.Arg13Gly	missense	Exon 1 of 28	ENSP00000540995.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1359958 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 670696

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28906

American (AMR) AF: 0.0000310 AC: 1 AN: 32250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24212

East Asian (EAS) AF: 0.00 AC: 0 AN: 31846

South Asian (SAS) AF: 0.00 AC: 0 AN: 76602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5064

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1064650

Other (OTH) AF: 0.00 AC: 0 AN: 56564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.035
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.081
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.30
MutPred		0.34		Loss of methylation at R13 (P = 0.0027)
MVP		0.47
MPC		0.92
ClinPred		0.96	D
GERP RS		3.0
PromoterAI		0.022	Neutral
Varity_R		0.21
gMVP		0.61
Mutation Taster		=93/7	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: rs748655557; hg19: chr19-14017291;