X-49064575-C-A

Variant names:

• chrX-49064575-C-A
• rs374462954
• NM_001163321.4:c.635C>A

Variant summary

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

The NM_001163321.4(CCDC120):​c.635C>A​(p.Pro212Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000938 in 1,066,565 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. P212L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: CCDC120 NM_001163321.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• Publications: 0 publications found

Genes affected

CCDC120 (HGNC:28910): (coiled-coil domain containing 120) This gene encodes a protein that contains a coiled-coil domain. Several alternatively spliced transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

CCDC120 Gene-Disease associations (from GenCC):

• osteopetrosis

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05240959).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163321.4. 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
	CCDC120	NM_001163321.4	MANE Select	c.635C>A	p.Pro212Gln	missense	Exon 6 of 11	NP_001156793.2	Q96HB5-4
	CCDC120	NM_001163322.2		c.494C>A	p.Pro165Gln	missense	Exon 6 of 11	NP_001156794.1	Q96HB5-5
	CCDC120	NM_001271835.1		c.530C>A	p.Pro177Gln	missense	Exon 6 of 10	NP_001258764.1	Q96HB5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC120	ENST00000603986.6	TSL:2 MANE Select	c.635C>A	p.Pro212Gln	missense	Exon 6 of 11	ENSP00000474071.1	Q96HB5-4
	CCDC120	ENST00000606812.5	TSL:1	c.530C>A	p.Pro177Gln	missense	Exon 6 of 10	ENSP00000475676.1	Q96HB5-1
	CCDC120	ENST00000603906.2	TSL:2	c.494C>A	p.Pro165Gln	missense	Exon 6 of 11	ENSP00000474713.2	Q96HB5-5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.38e-7 AC: 1 AN: 1066565 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 347601

⚠️ 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: 25513

American (AMR) AF: 0.0000331 AC: 1 AN: 30230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18787

East Asian (EAS) AF: 0.00 AC: 0 AN: 28115

South Asian (SAS) AF: 0.00 AC: 0 AN: 50653

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3957

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826299

Other (OTH) AF: 0.00 AC: 0 AN: 44867

⚠️ 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.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.75
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.77	N
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.036
Sift	Benign	0.50	T
Sift4G	Benign	0.16	T
Polyphen		0.97	D
Vest4		0.19
MutPred		0.27		Gain of sheet (P = 0.0266)
MVP		0.093
ClinPred		0.065	T
GERP RS		3.1
Varity_R		0.075
gMVP		0.31
Mutation Taster		=100/0	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: rs374462954; hg19: chrX-48922106;