15-74330208-G-T

Variant names:

• chr15-74330208-G-T
• rs2277604
• NM_025055.5:c.1310G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025055.5(CCDC33):​c.1310G>T​(p.Arg437Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,607,958 control chromosomes in the GnomAD database, including 1,243 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R437W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (91 hom., cov: 31)
  • Exomes 𝑓: 0.036 (1152 hom.)
• Consequence: CCDC33 NM_025055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.226
• Publications: 11 publications found

Genes affected

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001389116).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC33	NM_025055.5	MANE Select	c.1310G>T	p.Arg437Leu	missense	Exon 12 of 19	NP_079331.3
	CCDC33	NM_182791.4		c.89G>T	p.Arg30Leu	missense	Exon 2 of 9	NP_877592.2	Q8N5R6-5
	CCDC33	NM_001287181.2		c.89G>T	p.Arg30Leu	missense	Exon 2 of 8	NP_001274110.1	Q8N5R6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC33	ENST00000398814.8	TSL:2 MANE Select	c.1310G>T	p.Arg437Leu	missense	Exon 12 of 19	ENSP00000381795.3	Q8N5R6-6
	CCDC33	ENST00000558659.5	TSL:1	c.950G>T	p.Arg317Leu	missense	Exon 9 of 17	ENSP00000453542.1	H0YMB8
	CCDC33	ENST00000268082.4	TSL:1	c.89G>T	p.Arg30Leu	missense	Exon 2 of 9	ENSP00000268082.4	Q8N5R6-5

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4378 AN: 151918 Hom.: 92 Cov.: 31

Gnomad AFR AF: 0.00709

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.0854

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0369

Gnomad OTH AF: 0.0345

GnomAD2 exomes AF: 0.0345 AC: 8487 AN: 246134 AF XY: 0.0352

Gnomad AFR exome AF: 0.00598

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0434

Gnomad EAS exome AF: 0.0928

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0362

Gnomad OTH exome AF: 0.0421

GnomAD4 exome AF: 0.0362 AC: 52647 AN: 1455920 Hom.: 1152 Cov.: 31 AF XY: 0.0363 AC XY: 26253 AN XY: 723580

African (AFR) AF: 0.00761 AC: 254 AN: 33360

American (AMR) AF: 0.0218 AC: 966 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.0462 AC: 1196 AN: 25896

East Asian (EAS) AF: 0.0861 AC: 3404 AN: 39552

South Asian (SAS) AF: 0.0334 AC: 2866 AN: 85754

European-Finnish (FIN) AF: 0.0109 AC: 579 AN: 53066

Middle Eastern (MID) AF: 0.103 AC: 577 AN: 5622

European-Non Finnish (NFE) AF: 0.0365 AC: 40501 AN: 1108318

Other (OTH) AF: 0.0383 AC: 2304 AN: 60112

GnomAD4 genome AF: 0.0288 AC: 4374 AN: 152038 Hom.: 91 Cov.: 31 AF XY: 0.0284 AC XY: 2113 AN XY: 74320

African (AFR) AF: 0.00707 AC: 293 AN: 41464

American (AMR) AF: 0.0363 AC: 555 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3472

East Asian (EAS) AF: 0.0855 AC: 437 AN: 5110

South Asian (SAS) AF: 0.0383 AC: 185 AN: 4826

European-Finnish (FIN) AF: 0.00877 AC: 93 AN: 10602

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0369 AC: 2505 AN: 67976

Other (OTH) AF: 0.0347 AC: 73 AN: 2106

Alfa AF: 0.0369 Hom.: 369

Bravo AF: 0.0304

TwinsUK AF: 0.0386 AC: 143

ALSPAC AF: 0.0374 AC: 144

ESP6500AA AF: 0.00619 AC: 25

ESP6500EA AF: 0.0385 AC: 321

ExAC AF: 0.0355 AC: 4290

Asia WGS AF: 0.0510 AC: 176 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.97
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.23
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.044
Sift	Benign	0.059	T
Sift4G	Benign	0.27	T
Polyphen		0.41	B
Vest4		0.049
MPC		0.22
ClinPred		0.031	T
GERP RS		-1.0
gMVP		0.054
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2277604; hg19: chr15-74622549;