8-27765231-T-C

Variant names:

• chr8-27765231-T-C
• rs762598226
• NM_018246.3:c.49A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018246.3(CCDC25):​c.49A>G​(p.Ile17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,502,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CCDC25 NM_018246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69
• Publications: 1 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1074608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC25	NM_018246.3	c.49A>G	p.Ile17Val	missense_variant	Exon 2 of 9	ENST00000356537.9	NP_060716.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC25	ENST00000356537.9	c.49A>G	p.Ile17Val	missense_variant	Exon 2 of 9	1	NM_018246.3	ENSP00000348933.4

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 23 AN: 192348 AF XY: 0.000115

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000790

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 281 AN: 1350100 Hom.: 0 Cov.: 28 AF XY: 0.000198 AC XY: 132 AN XY: 666326

African (AFR) AF: 0.00 AC: 0 AN: 30372

American (AMR) AF: 0.0000575 AC: 2 AN: 34796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23814

East Asian (EAS) AF: 0.00 AC: 0 AN: 36444

South Asian (SAS) AF: 0.0000257 AC: 2 AN: 77918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5358

European-Non Finnish (NFE) AF: 0.000257 AC: 267 AN: 1039116

Other (OTH) AF: 0.000181 AC: 10 AN: 55282

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000999 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49A>G (p.I17V) alteration is located in exon 2 (coding exon 2) of the CCDC25 gene. This alteration results from a A to G substitution at nucleotide position 49, causing the isoleucine (I) at amino acid position 17 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.056	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		1.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.82	N;.
REVEL	Benign	0.063
Sift	Benign	0.042	D;.
Sift4G	Benign	0.18	T;.
Polyphen		0.0030	B;.
Vest4		0.24
MVP		0.32
MPC		0.43
ClinPred		0.031	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.46
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs762598226; hg19: chr8-27622748;