chr5-69307966-G-C

Variant names:

• chr5-69307966-G-C
• rs1757598309
• NM_176816.5:c.516C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_176816.5(CCDC125):​c.516C>G​(p.Asn172Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCDC125 NM_176816.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• Publications: 0 publications found

Genes affected

CCDC125 (HGNC:28924): (coiled-coil domain containing 125) Enables identical protein binding activity. Involved in activation of GTPase activity; negative regulation of Rho protein signal transduction; and negative regulation of cell motility. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029822588).
• BP6: Variant 5-69307966-G-C is Benign according to our data. Variant chr5-69307966-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3138319.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176816.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC125	NM_176816.5	MANE Select	c.516C>G	p.Asn172Lys	missense	Exon 5 of 12	NP_789786.2	Q86Z20-1
	CCDC125	NM_001297697.2		c.141C>G	p.Asn47Lys	missense	Exon 6 of 13	NP_001284626.1	Q86Z20-2
	CCDC125	NM_001297696.2		c.513C>G	p.Asn171Lys	missense	Exon 5 of 11	NP_001284625.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC125	ENST00000396496.7	TSL:5 MANE Select	c.516C>G	p.Asn172Lys	missense	Exon 5 of 12	ENSP00000379754.2	Q86Z20-1
	CCDC125	ENST00000396499.5	TSL:1	c.516C>G	p.Asn172Lys	missense	Exon 4 of 11	ENSP00000379756.1	Q86Z20-1
	CCDC125	ENST00000460090.5	TSL:1	n.229-7839C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461178 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726944

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

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111426

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.30
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.055	N
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.6	N
PhyloP100		1.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.029
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.35		Gain of ubiquitination at N172 (P = 0.0276)
MVP		0.081
MPC		0.074
ClinPred		0.070	T
GERP RS		2.8
Varity_R		0.060
gMVP		0.054
Mutation Taster		=96/4	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: rs1757598309; hg19: chr5-68603793;