chr3-46925534-C-T

Variant names:

• chr3-46925534-C-T
• rs376223547
• NM_001277074.2:c.166G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001277074.2(CCDC12):​c.166G>A​(p.Glu56Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCDC12 NM_001277074.2 missense, splice_region
• Scores: Splicing: ADA: 0.01360
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.10

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34804678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC12	NM_001277074.2	c.166G>A	p.Glu56Lys	missense_variant, splice_region_variant	Exon 3 of 7	ENST00000683445.1	NP_001264003.1
CCDC12	NM_144716.6	c.205G>A	p.Glu69Lys	missense_variant, splice_region_variant	Exon 4 of 8		NP_653317.2
CCDC12	NR_102269.2	n.219G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC12	ENST00000683445.1	c.166G>A	p.Glu56Lys	missense_variant, splice_region_variant	Exon 3 of 7		NM_001277074.2	ENSP00000508011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1420674 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 700454

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.0039	T;.;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.63	N;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.080	.;N;.;.
REVEL	Benign	0.20
Sift	Benign	0.72	.;T;.;.
Sift4G	Benign	0.91	T;T;T;.
Polyphen		0.72	P;.;.;.
Vest4		0.49
MutPred		0.43		Gain of ubiquitination at E56 (P = 0.0048);.;Gain of ubiquitination at E56 (P = 0.0048);Gain of ubiquitination at E56 (P = 0.0048);
MVP		0.25
MPC		0.57
ClinPred		0.94	D
GERP RS		5.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.17
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.13
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: rs376223547; hg19: chr3-46967024;