14-59525337-T-C

Variant names:

• chr14-59525337-T-C
• NM_001164399.2:c.1940A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001164399.2(CCDC175):​c.1940A>G​(p.Tyr647Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCDC175 NM_001164399.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

Genes affected

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

ENSG00000258782 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC175	NM_001164399.2	c.1940A>G	p.Tyr647Cys	missense_variant	Exon 16 of 20	ENST00000537690.7	NP_001157871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC175	ENST00000537690.7	c.1940A>G	p.Tyr647Cys	missense_variant	Exon 16 of 20	5	NM_001164399.2	ENSP00000453940.1
CCDC175	ENST00000281581.5	c.1940A>G	p.Tyr647Cys	missense_variant	Exon 16 of 20	5		ENSP00000452964.1
ENSG00000258782	ENST00000554253.1	n.101A>G		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1352028 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 667250

African (AFR) AF: 0.00 AC: 0 AN: 28850

American (AMR) AF: 0.00 AC: 0 AN: 26910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24218

East Asian (EAS) AF: 0.00 AC: 0 AN: 34560

South Asian (SAS) AF: 0.00 AC: 0 AN: 73494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5418

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067342

Other (OTH) AF: 0.00 AC: 0 AN: 56594

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1940A>G (p.Y647C) alteration is located in exon 16 (coding exon 16) of the CCDC175 gene. This alteration results from a A to G substitution at nucleotide position 1940, causing the tyrosine (Y) at amino acid position 647 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	0.13
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.56	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		1.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D;D
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.092	T;T
Vest4		0.74
MVP		0.32
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.34
gMVP		0.11
Mutation Taster		=87/13	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

hg19: chr14-59992055;