17-63756292-A-G

Position:

• chr17-63756292-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020198.3(CCDC47):​c.896T>C​(p.Leu299Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CCDC47 NM_020198.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.86

Genes affected

CCDC47 (HGNC:24856): (coiled-coil domain containing 47) Enables protein folding chaperone and ribosome binding activity. Involved in ERAD pathway; endoplasmic reticulum calcium ion homeostasis; and protein insertion into ER membrane. Located in endoplasmic reticulum. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

CCDC47 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC47	NM_020198.3	c.896T>C	p.Leu299Ser	missense_variant	8/13	ENST00000225726.10	NP_064583.2
CCDC47	XM_005257527.3	c.896T>C	p.Leu299Ser	missense_variant	8/13		XP_005257584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC47	ENST00000225726.10	c.896T>C	p.Leu299Ser	missense_variant	8/13	1	NM_020198.3	ENSP00000225726.5
CCDC47	ENST00000403162.7	c.896T>C	p.Leu299Ser	missense_variant	9/14	2		ENSP00000384888.3
CCDC47	ENST00000582252.1	c.896T>C	p.Leu299Ser	missense_variant	8/12	2		ENSP00000463577.1
CCDC47	ENST00000582331.2	n.535T>C		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CCDC47-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2022

The CCDC47 c.896T>C variant is predicted to result in the amino acid substitution p.Leu299Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.77	P;P;P
Vest4		0.92
MutPred		0.72		Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);
MVP		0.85
MPC		0.65
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs2039206079; hg19: chr17-61833652;