19-13909859-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017721.5(CC2D1A):c.97A>T(p.Met33Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CC2D1A NM_017721.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094427526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D1A	NM_017721.5	c.97A>T	p.Met33Leu	missense_variant	2/29	ENST00000318003.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D1A	ENST00000318003.11	c.97A>T	p.Met33Leu	missense_variant	2/29	1	NM_017721.5	P3
CC2D1A	ENST00000589606.5	c.97A>T	p.Met33Leu	missense_variant	2/29	1		A1
CC2D1A	ENST00000585896.5	n.336A>T		non_coding_transcript_exon_variant	2/10	2
CC2D1A	ENST00000680439.1	n.255A>T		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428896 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 706784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.97A>T (p.M33L) alteration is located in exon 2 (coding exon 2) of the CC2D1A gene. This alteration results from a A to T substitution at nucleotide position 97, causing the methionine (M) at amino acid position 33 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Benign	0.86
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.96	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.96	N;.
REVEL	Benign	0.029
Sift	Benign	0.64	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.84	P;B
Vest4		0.24
MutPred		0.17		Gain of glycosylation at S28 (P = 0.1975);Gain of glycosylation at S28 (P = 0.1975);
MVP		0.21
MPC		0.20
ClinPred		0.12	T
GERP RS		3.3
Varity_R		0.094
gMVP		0.26

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-14020672;