14-59521594-C-G

Position:

• chr14-59521594-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001164399.2(CCDC175):​c.2078G>C​(p.Arg693Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC175 NM_001164399.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.552

Genes affected

CCDC175 (HGNC:19847): (coiled-coil domain containing 175)

ENSG00000258782 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.063666224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC175	NM_001164399.2	c.2078G>C	p.Arg693Pro	missense_variant	17/20	ENST00000537690.7	NP_001157871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC175	ENST00000537690.7	c.2078G>C	p.Arg693Pro	missense_variant	17/20	5	NM_001164399.2	ENSP00000453940.1
CCDC175	ENST00000281581.5	c.2078G>C	p.Arg693Pro	missense_variant	17/20	5		ENSP00000452964.1
ENSG00000258782	ENST00000554253.1	n.239G>C		non_coding_transcript_exon_variant	2/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.2078G>C (p.R693P) alteration is located in exon 17 (coding exon 17) of the CCDC175 gene. This alteration results from a G to C substitution at nucleotide position 2078, causing the arginine (R) at amino acid position 693 to be replaced by a proline (P). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.52
DEOGEN2	Benign	0.0044	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.87	N;N
Sift	Benign	0.16	T;T
Sift4G	Benign	0.32	T;T
Vest4		0.23
MVP		0.13
ClinPred		0.056	T
GERP RS		1.6
Varity_R		0.17
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs73305628; hg19: chr14-59988312;