chr15-74330208-G-T

Position:

• chr15-74330208-G-T

Variant summary

Our verdict is Benign. Variant got -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. 11/17 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC33	NM_025055.5	c.1310G>T	p.Arg437Leu	missense_variant	12/19	ENST00000398814.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC33	ENST00000398814.8	c.1310G>T	p.Arg437Leu	missense_variant	12/19	2	NM_025055.5	P2

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

GnomAD3 exomes AF: 0.0345 AC: 8487 AN: 246134 Hom.: 216 AF XY: 0.0352 AC XY: 4703 AN XY: 133624

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 SAS exome AF: 0.0359

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

Gnomad4 AFR exome AF: 0.00761

Gnomad4 AMR exome AF: 0.0218

Gnomad4 ASJ exome AF: 0.0462

Gnomad4 EAS exome AF: 0.0861

Gnomad4 SAS exome AF: 0.0334

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0365

Gnomad4 OTH exome AF: 0.0383

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

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.0363

Gnomad4 ASJ AF: 0.0559

Gnomad4 EAS AF: 0.0855

Gnomad4 SAS AF: 0.0383

Gnomad4 FIN AF: 0.00877

Gnomad4 NFE AF: 0.0369

Gnomad4 OTH AF: 0.0347

Alfa AF: 0.0379 Hom.: 202

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 v4.3

Name	Calibrated prediction	Score	Prediction
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;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.044
Sift	Benign	0.059	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.41	B;B;B
Vest4		0.049
MPC		0.22
ClinPred		0.031	T
GERP RS		-1.0
gMVP		0.054

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

Publications

LitVar

Other links and lift over

dbSNP: rs2277604; hg19: chr15-74622549;