3-46922254-C-A

Position:

• chr3-46922254-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001277074.2(CCDC12):​c.400G>T​(p.Ala134Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCDC12 NM_001277074.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.41

Genes affected

CCDC12 (HGNC:28332): (coiled-coil domain containing 12) Predicted to be part of U2-type spliceosomal complex and post-mRNA release spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC12	NM_001277074.2	c.400G>T	p.Ala134Ser	missense_variant	6/7	ENST00000683445.1	NP_001264003.1
CCDC12	NM_144716.6	c.439G>T	p.Ala147Ser	missense_variant	7/8		NP_653317.2
CCDC12	NR_102269.2	n.453G>T		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC12	ENST00000683445.1	c.400G>T	p.Ala134Ser	missense_variant	6/7		NM_001277074.2	ENSP00000508011.1
CCDC12	ENST00000292314.6	c.439G>T	p.Ala147Ser	missense_variant	7/8	5		ENSP00000292314.2
CCDC12	ENST00000425441.5	c.400G>T	p.Ala134Ser	missense_variant	8/9	5		ENSP00000416263.2
CCDC12	ENST00000604367.1	n.1906G>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2024

The c.439G>T (p.A147S) alteration is located in exon 6 (coding exon 6) of the CCDC12 gene. This alteration results from a G to T substitution at nucleotide position 439, causing the alanine (A) at amino acid position 147 to be replaced by a serine (S). 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	0.30
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.70	N;D
REVEL	Pathogenic	0.72
Sift	Benign	0.40	T;D
Sift4G	Benign	0.062	T;T
Polyphen		0.99	D;.
Vest4		0.86
MutPred		0.78		Gain of glycosylation at T131 (P = 0.0064);.;
MVP		0.55
MPC		0.67
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.42

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: chr3-46963744;