15-74244085-T-G

Position:

• chr15-74244085-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025055.5(CCDC33):​c.122T>G​(p.Leu41Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCDC33 NM_025055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

Genes affected

CCDC33 (HGNC:26552): (coiled-coil domain containing 33) Predicted to be active in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

CCDC33 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC33	NM_025055.5	c.122T>G	p.Leu41Arg	missense_variant	2/19	ENST00000398814.8	NP_079331.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC33	ENST00000398814.8	c.122T>G	p.Leu41Arg	missense_variant	2/19	2	NM_025055.5	ENSP00000381795.3
CCDC33	ENST00000635913.2	c.776T>G	p.Leu259Arg	missense_variant	3/20	5		ENSP00000490425.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461752 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 20, 2024

The c.122T>G (p.L41R) alteration is located in exon 2 (coding exon 2) of the CCDC33 gene. This alteration results from a T to G substitution at nucleotide position 122, causing the leucine (L) at amino acid position 41 to be replaced by an arginine (R). 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
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.46	T
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0030	.;D
Polyphen		0.99	.;D
Vest4		0.90
MutPred		0.60		.;Loss of sheet (P = 0.0126);
MVP		0.78
MPC		0.15
ClinPred		0.80	D
GERP RS		4.8
gMVP		0.76

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: rs2075440939; hg19: chr15-74536426;