NM_153634.3:c.311G>C

Variant names:

• chr12-38839935-C-G
• rs778884699
• NM_153634.3:c.311G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_153634.3(CPNE8):​c.311G>C​(p.Ser104Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,427,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. S104N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CPNE8 NM_153634.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40

Genes affected

CPNE8 (HGNC:23498): (copine 8) Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm. This gene is one of several genes that encode a calcium-dependent protein containing two N-terminal type II C2 domains and an integrin A domain-like sequence in the C-terminus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CPNE8_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40838706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE8	NM_153634.3	c.311G>C	p.Ser104Thr	missense_variant	Exon 5 of 20	ENST00000331366.10	NP_705898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPNE8	ENST00000331366.10	c.311G>C	p.Ser104Thr	missense_variant	Exon 5 of 20	1	NM_153634.3	ENSP00000329748.5
CPNE8	ENST00000360449.3	c.275G>C	p.Ser92Thr	missense_variant	Exon 5 of 20	2		ENSP00000353633.3
CPNE8	ENST00000550863.1	c.-173G>C		5_prime_UTR_variant	Exon 5 of 8	4		ENSP00000447761.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 240990 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1427932 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 710128

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: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.051	T;.
Eigen	Benign	-0.053
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.89	L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.18
Sift	Benign	0.74	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.081	B;.
Vest4		0.61
MutPred		0.36		Gain of phosphorylation at S104 (P = 0.078);.;
MVP		0.71
MPC		0.80
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.18
gMVP		0.45

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: rs778884699; hg19: chr12-39233737;