X-49065486-C-T

Variant names:

• chrX-49065486-C-T
• rs1366838657
• NM_001163321.4:c.820C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1876418).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC120	NM_001163321.4	c.820C>T	p.Arg274Cys	missense_variant	Exon 8 of 11	ENST00000603986.6	NP_001156793.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC120	ENST00000603986.6	c.820C>T	p.Arg274Cys	missense_variant	Exon 8 of 11	2	NM_001163321.4	ENSP00000474071.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000551 AC: 6 AN: 1088679 Hom.: 0 Cov.: 32 AF XY: 0.00000561 AC XY: 2 AN XY: 356579

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000715

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.715C>T (p.R239C) alteration is located in exon 8 (coding exon 6) of the CCDC120 gene. This alteration results from a C to T substitution at nucleotide position 715, causing the arginine (R) at amino acid position 239 to be replaced by a cysteine (C). 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	0.19
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;T;T;.;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	.;.;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.9	.;.;.;.;D
REVEL	Benign	0.11
Sift	Pathogenic	0.0	.;.;.;.;D
Sift4G	Benign	0.083	T;T;T;T;T
Polyphen		1.0	D;D;D;.;.
Vest4		0.36
MutPred		0.20		Loss of phosphorylation at S241 (P = 0.0554);Loss of phosphorylation at S241 (P = 0.0554);Loss of phosphorylation at S241 (P = 0.0554);.;.;
MVP		0.19
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.40
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs1366838657; hg19: chrX-48923017;