22-30366134-G-T

Variant summary

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

The NM_001017437.5(CCDC157):c.134G>T(p.Arg45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CCDC157 NM_001017437.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

Genes affected

CCDC157 (HGNC:33854): (coiled-coil domain containing 157)

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=0.23046395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC157	NM_001017437.5	c.134G>T	p.Arg45Leu	missense_variant	3/12	ENST00000338306.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC157	ENST00000338306.8	c.134G>T	p.Arg45Leu	missense_variant	3/12	5	NM_001017437.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250620 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461238 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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

Jan 23, 2023

The c.134G>T (p.R45L) alteration is located in exon 3 (coding exon 1) of the CCDC157 gene. This alteration results from a G to T substitution at nucleotide position 134, causing the arginine (R) at amino acid position 45 to be replaced by a leucine (L). 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	-0.072	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.088	T;T;T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;.;T;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.015	D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		0.33	.;B;B;.;.
Vest4		0.28
MutPred		0.32		Gain of ubiquitination at K41 (P = 0.0506);Gain of ubiquitination at K41 (P = 0.0506);Gain of ubiquitination at K41 (P = 0.0506);Gain of ubiquitination at K41 (P = 0.0506);Gain of ubiquitination at K41 (P = 0.0506);
MVP		0.37
MPC		0.13
ClinPred		0.90	D
GERP RS		3.1
Varity_R		0.17
gMVP		0.50

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: rs201763455; hg19: chr22-30762123;