chr14-59525316-T-G

Variant names:

• chr14-59525316-T-G
• rs755728050
• NM_001164399.2:c.1961A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164399.2(CCDC175):​c.1961A>C​(p.Asp654Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,462,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. D654E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CCDC175 NM_001164399.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09971711).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC175	NM_001164399.2	c.1961A>C	p.Asp654Ala	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.1961A>C	p.Asp654Ala	missense_variant	Exon 16 of 20	5	NM_001164399.2	ENSP00000453940.1
CCDC175	ENST00000281581.5	c.1961A>C	p.Asp654Ala	missense_variant	Exon 16 of 20	5		ENSP00000452964.1
ENSG00000258782	ENST00000554253.1	n.122A>C		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 86168 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000496 AC: 65 AN: 1310404 Hom.: 0 Cov.: 27 AF XY: 0.0000388 AC XY: 25 AN XY: 644306

African (AFR) AF: 0.0000372 AC: 1 AN: 26858

American (AMR) AF: 0.00 AC: 0 AN: 18442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22328

East Asian (EAS) AF: 0.00 AC: 0 AN: 32686

South Asian (SAS) AF: 0.00 AC: 0 AN: 66762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4942

European-Non Finnish (NFE) AF: 0.0000590 AC: 62 AN: 1050108

Other (OTH) AF: 0.0000366 AC: 2 AN: 54582

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1961A>C (p.D654A) alteration is located in exon 16 (coding exon 16) of the CCDC175 gene. This alteration results from a A to C substitution at nucleotide position 1961, causing the aspartic acid (D) at amino acid position 654 to be replaced by an alanine (A). 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	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.67
DEOGEN2	Benign	0.0082	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;.
PhyloP100		2.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N
Sift	Benign	0.32	T;T
Sift4G	Benign	0.37	T;T
Vest4		0.14
MVP		0.31
ClinPred		0.056	T
GERP RS		3.6
Varity_R		0.052
gMVP		0.093
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs755728050; hg19: chr14-59992034;