chr3-46976723-T-C

Position:

• chr3-46976723-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001277074.2(CCDC12):​c.10A>G​(p.Thr4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: CCDC12 NM_001277074.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.42

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04070452).
• BP6: Variant 3-46976723-T-C is Benign according to our data. Variant chr3-46976723-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3138287.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC12	NM_001277074.2	c.10A>G	p.Thr4Ala	missense_variant	1/7	ENST00000683445.1	NP_001264003.1
CCDC12	NM_144716.6	c.49A>G	p.Thr17Ala	missense_variant	2/8		NP_653317.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC12	ENST00000683445.1	c.10A>G	p.Thr4Ala	missense_variant	1/7		NM_001277074.2	ENSP00000508011	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 35

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.0070
DANN	Benign	0.75
DEOGEN2	Benign	0.0065	T;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.33	T;T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.041	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.47	.;N;.;.
REVEL	Benign	0.012
Sift	Benign	0.23	.;T;.;.
Sift4G	Benign	0.57	T;T;T;.
Polyphen		0.0	B;.;.;.
Vest4		0.034
MutPred		0.18		Gain of helix (P = 0.0093);.;Gain of helix (P = 0.0093);Gain of helix (P = 0.0093);
MVP		0.10
MPC		0.21
ClinPred		0.086	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.11

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: chr3-47018213;