14-59505279-G-T

Variant names:

• chr14-59505279-G-T
• rs138609862
• NM_001164399.2:c.2342C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001164399.2(CCDC175):​c.2342C>A​(p.Pro781Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,509,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: CCDC175 NM_001164399.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.214
• Publications: 1 publications found

Genes affected

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

JKAMP (HGNC:20184): (JNK1/MAPK8 associated membrane protein) Enables ubiquitin protein ligase binding activity. Involved in ubiquitin-dependent ERAD pathway. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000258782 (HGNC:):

L3HYPDH (HGNC:20488): (trans-L-3-hydroxyproline dehydratase) The protein encoded by this gene is a dehydratase that converts trans-3-hydroxy-L-proline to delta(1)-pyrroline-2-carboxylate. This enzyme may function to degrade dietary proteins that contain trans-3-hydroxy-L-proline as well as other proteins such as collagen IV. The encoded protein can be converted to an epimerase by changing a threonine to a cysteine at a catalytic site. [provided by RefSeq, Sep 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03286177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC175	NM_001164399.2	c.2342C>A	p.Pro781Gln	missense_variant	Exon 20 of 20	ENST00000537690.7	NP_001157871.1
JKAMP	NM_016475.5	c.*1207G>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000616435.5	NP_057559.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC175	ENST00000537690.7	c.2342C>A	p.Pro781Gln	missense_variant	Exon 20 of 20	5	NM_001164399.2	ENSP00000453940.1
JKAMP	ENST00000616435.5	c.*1207G>T		3_prime_UTR_variant	Exon 7 of 7	5	NM_016475.5	ENSP00000479775.2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000515

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000228 AC: 31 AN: 136024 AF XY: 0.000301

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.000245

GnomAD4 exome AF: 0.000352 AC: 478 AN: 1357184 Hom.: 0 Cov.: 25 AF XY: 0.000322 AC XY: 216 AN XY: 669892

African (AFR) AF: 0.0000322 AC: 1 AN: 31012

American (AMR) AF: 0.000115 AC: 4 AN: 34746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24606

East Asian (EAS) AF: 0.00 AC: 0 AN: 35360

South Asian (SAS) AF: 0.00 AC: 0 AN: 74884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 0.000441 AC: 467 AN: 1060120

Other (OTH) AF: 0.000106 AC: 6 AN: 56762

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74430

African (AFR) AF: 0.0000481 AC: 2 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.000104 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2342C>A (p.P781Q) alteration is located in exon 20 (coding exon 20) of the CCDC175 gene. This alteration results from a C to A substitution at nucleotide position 2342, causing the proline (P) at amino acid position 781 to be replaced by a glutamine (Q). 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	0.18
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.21
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.040	N
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.17
MVP		0.030
ClinPred		0.094	T
GERP RS		3.4
Varity_R		0.036
gMVP		0.051
Mutation Taster		=90/10	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

dbSNP: rs138609862; hg19: chr14-59971997;