8-27748171-G-C

Variant names:

• chr8-27748171-G-C
• rs757755754
• NM_018246.3:c.457C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018246.3(CCDC25):​c.457C>G​(p.Arg153Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R153H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCDC25 NM_018246.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15
• Publications: 0 publications found

Genes affected

CCDC25 (HGNC:25591): (coiled-coil domain containing 25) Enables DNA binding activity. Involved in positive regulation of cell motility. Located in endomembrane system. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000253875 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2796765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC25	NM_018246.3	c.457C>G	p.Arg153Gly	missense_variant	Exon 7 of 9	ENST00000356537.9	NP_060716.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC25	ENST00000356537.9	c.457C>G	p.Arg153Gly	missense_variant	Exon 7 of 9	1	NM_018246.3	ENSP00000348933.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461494 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.021
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		4.1
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.083
Sift	Benign	0.11	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.0020	B;.
Vest4		0.48
MutPred		0.20		Loss of MoRF binding (P = 0.0557);.;
MVP		0.42
MPC		0.63
ClinPred		0.94	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.29
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs757755754; hg19: chr8-27605688; COSMIC: COSV62958386;