chr2-74474965-C-G

Position:

• chr2-74474965-C-G

Variant summary

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

The NM_001365575.2(CCDC142):​c.1947G>C​(p.Leu649Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,616 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: 0.0000014 (0 hom.)
• Consequence: CCDC142 NM_001365575.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.505

Genes affected

CCDC142 (HGNC:25889): (coiled-coil domain containing 142)

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=0.17545882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC142	NM_001365575.2	c.1947G>C	p.Leu649Phe	missense_variant	8/9	ENST00000393965.8
CCDC142	NM_032779.4	c.1926G>C	p.Leu642Phe	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC142	ENST00000393965.8	c.1947G>C	p.Leu649Phe	missense_variant	8/9	1	NM_001365575.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458616 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725494

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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.: 32

Bravo AF: 0.00000378

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

Feb 21, 2024

The c.1926G>C (p.L642F) alteration is located in exon 8 (coding exon 8) of the CCDC142 gene. This alteration results from a G to C substitution at nucleotide position 1926, causing the leucine (L) at amino acid position 642 to be replaced by a phenylalanine (F). 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	0.24
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.89	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.048
Sift	Benign	0.069	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.18	B;B
Vest4		0.28
MutPred		0.16		Loss of disorder (P = 0.0943);.;
MVP		0.69
MPC		0.85
ClinPred		0.88	D
GERP RS		1.8
Varity_R		0.11
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1672285751; hg19: chr2-74702092;