4-47463605-G-C

Variant names:

• chr4-47463605-G-C
• rs1002034383
• NM_017845.5:c.47C>G

Variant summary

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

The NM_017845.5(COMMD8):​c.47C>G​(p.Pro16Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,546,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P16Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: COMMD8 NM_017845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75

Genes affected

COMMD8 (HGNC:26036): (COMM domain containing 8) The protein encoded by this gene binds coiled-coil domain-containing protein 22 (CCDC22), and this complex can regulate the turnover of I-kappa-B and the activation of NF-kappa-B. [provided by RefSeq, Jul 2016]

ENSG00000282904 (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, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMMD8	NM_017845.5	c.47C>G	p.Pro16Arg	missense_variant	Exon 1 of 5	ENST00000381571.6	NP_060315.1
COMMD8	NM_001329668.2	c.47C>G	p.Pro16Arg	missense_variant	Exon 1 of 5		NP_001316597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMMD8	ENST00000381571.6	c.47C>G	p.Pro16Arg	missense_variant	Exon 1 of 5	1	NM_017845.5	ENSP00000370984.4
COMMD8	ENST00000509220.1	n.61C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000282904	ENST00000634784.2	n.16G>C		non_coding_transcript_exon_variant	Exon 1 of 3	3
ENSG00000282904	ENST00000635489.1	n.-179G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152268 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000208 AC: 3 AN: 144036 Hom.: 0 AF XY: 0.0000129 AC XY: 1 AN XY: 77600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000208 AC: 29 AN: 1394530 Hom.: 0 Cov.: 31 AF XY: 0.0000174 AC XY: 12 AN XY: 687776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000281

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000223

Gnomad4 OTH exome AF: 0.0000519

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152268 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.81		Loss of helix (P = 0.0304);
MVP		0.66
MPC		0.59
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.42
gMVP		0.46

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: rs1002034383; hg19: chr4-47465622;