Genetic Variant CCDC120:p.Arg274Cys (chrX-49065486-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001163321.4(CCDC120):c.820C>T(p.Arg274Cys) 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 1,088,679 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R274H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 2 hem. )

Consequence

CCDC120
NM_001163321.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Publications

0 publications found

Variant links:

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

CCDC120 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1876418).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC120	NM_001163321.4	MANE Select	c.820C>T	p.Arg274Cys	missense	Exon 8 of 11	NP_001156793.2	Q96HB5-4
CCDC120	NM_001163322.2		c.679C>T	p.Arg227Cys	missense	Exon 8 of 11	NP_001156794.1	Q96HB5-5
CCDC120	NM_001271835.1		c.715C>T	p.Arg239Cys	missense	Exon 8 of 10	NP_001258764.1	Q96HB5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC120	ENST00000603986.6	TSL:2 MANE Select	c.820C>T	p.Arg274Cys	missense	Exon 8 of 11	ENSP00000474071.1	Q96HB5-4
CCDC120	ENST00000606812.5	TSL:1	c.715C>T	p.Arg239Cys	missense	Exon 8 of 10	ENSP00000475676.1	Q96HB5-1
CCDC120	ENST00000603906.2	TSL:2	c.679C>T	p.Arg227Cys	missense	Exon 8 of 11	ENSP00000474713.2	Q96HB5-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000551

AC:

AN:

1088679

Hom.:

Cov.:

AF XY:

0.00000561

AC XY:

AN XY:

356579

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25976

American (AMR)

AF:

0.00

AC:

AN:

33020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18754

East Asian (EAS)

AF:

0.00

AC:

AN:

30104

South Asian (SAS)

AF:

0.00

AC:

AN:

52322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4062

European-Non Finnish (NFE)

AF:

0.00000715

AC:

AN:

838613

Other (OTH)

AF:

0.00

AC:

AN:

45662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.066

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.4

PhyloP100

2.0

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.11

Sift

Pathogenic

0.0

Sift4G

Benign

0.083

Polyphen

1.0

Vest4

0.36

MutPred

0.20

Loss of phosphorylation at S241 (P = 0.0554)

MVP

0.19

ClinPred

0.99

GERP RS

3.1

Varity_R

0.40

gMVP

0.46

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over