22-30369548-G-A

Variant summary

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

The NM_001017437.5(CCDC157):c.365G>A(p.Arg122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,450,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CCDC157 NM_001017437.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.837

Genes affected

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

KIAA1656 (HGNC:):

RNF215 (HGNC:33434): (ring finger protein 215) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in Golgi to vacuole transport; protein targeting to vacuole; and ubiquitin-dependent protein catabolic process. Predicted to be integral component of membrane. Predicted to be part of Golgi transport complex. Predicted to be active in endosome; membrane; and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2371811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC157	NM_001017437.5	c.365G>A	p.Arg122His	missense_variant	4/12	ENST00000338306.8
KIAA1656	NR_046312.1	n.6868C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC157	ENST00000338306.8	c.365G>A	p.Arg122His	missense_variant	4/12	5	NM_001017437.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000837 AC: 2 AN: 239084 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130082

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000302

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: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000551 AC: 8 AN: 1450654 Hom.: 0 Cov.: 31 AF XY: 0.00000554 AC XY: 4 AN XY: 721616

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000517

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 14, 2023

The c.365G>A (p.R122H) alteration is located in exon 4 (coding exon 2) of the CCDC157 gene. This alteration results from a G to A substitution at nucleotide position 365, causing the arginine (R) at amino acid position 122 to be replaced by a histidine (H). 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	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.014	T;T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.025	D;D;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.42
MutPred		0.54		Loss of MoRF binding (P = 0.0261);Loss of MoRF binding (P = 0.0261);Loss of MoRF binding (P = 0.0261);Loss of MoRF binding (P = 0.0261);
MVP		0.34
MPC		0.46
ClinPred		0.79	D
GERP RS		4.3
Varity_R		0.085
gMVP		0.23

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: rs753449486; hg19: chr22-30765537; COSMIC: COSV57838300; COSMIC: COSV57838300;