3-46976731-A-G

Variant names:

• chr3-46976731-A-G
• rs1248512160
• NM_001277074.2:c.2T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001277074.2(CCDC12):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,453,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CCDC12 NM_001277074.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC12	NM_001277074.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENST00000683445.1	NP_001264003.1
CCDC12	NM_144716.6	c.41T>C	p.Met14Thr	missense_variant	Exon 2 of 8		NP_653317.2
CCDC12	NR_102269.2	n.-230T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC12	ENST00000683445.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 7		NM_001277074.2	ENSP00000508011.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453820 Hom.: 0 Cov.: 34 AF XY: 0.00000277 AC XY: 2 AN XY: 722454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41T>C (p.M14T) alteration is located in exon 1 (coding exon 1) of the CCDC12 gene. This alteration results from a T to C substitution at nucleotide position 41, causing the methionine (M) at amino acid position 14 to be replaced by a threonine (T). 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
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.90	D;T;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.14	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.19	N;N;N;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.013	D;D;D;.
Sift4G	Pathogenic	0.0	D;T;D;.
Polyphen		0.93	P;.;.;.
Vest4		0.92
MutPred		0.96		Gain of glycosylation at T5 (P = 0.0313);.;Gain of glycosylation at T5 (P = 0.0313);Gain of glycosylation at T5 (P = 0.0313);
MVP		0.50
MPC		0.32
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs1248512160; hg19: chr3-47018221;