Genetic Variant NM_001286176.2:c.2396A>G (chr12-22470874-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001286176.2(C2CD5):c.2396A>G(p.Asn799Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. N799T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

C2CD5
NM_001286176.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.47

Publications

0 publications found

Variant links:

Genes affected

C2CD5 (HGNC:29062): (C2 calcium dependent domain containing 5) Enables calcium ion binding activity and calcium-dependent phospholipid binding activity. Involved in cellular response to insulin stimulus; intracellular protein transmembrane transport; and positive regulation of transport. Located in several cellular components, including centriolar satellite; cytoplasmic vesicle membrane; and ruffle membrane. [provided by Alliance of Genome Resources, Apr 2022]

C2CD5 links:

C2CD5-AS1 (HGNC:55961): (C2CD5 antisense RNA 1)

C2CD5-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19796675).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286176.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C2CD5	NM_001286176.2	MANE Select	c.2396A>G	p.Asn799Ser	missense	Exon 21 of 27	NP_001273105.1	Q86YS7-3
C2CD5	NM_001385322.1		c.2588A>G	p.Asn863Ser	missense	Exon 22 of 28	NP_001372251.1
C2CD5	NM_001385323.1		c.2435A>G	p.Asn812Ser	missense	Exon 22 of 28	NP_001372252.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C2CD5	ENST00000446597.6	TSL:1 MANE Select	c.2396A>G	p.Asn799Ser	missense	Exon 21 of 27	ENSP00000388756.1	Q86YS7-3
C2CD5	ENST00000536386.5	TSL:1	c.2402A>G	p.Asn801Ser	missense	Exon 22 of 28	ENSP00000439392.1	Q86YS7-4
C2CD5	ENST00000396028.6	TSL:1	c.2369A>G	p.Asn790Ser	missense	Exon 21 of 27	ENSP00000379345.2	Q86YS7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460558

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726628

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111074

Other (OTH)

AF:

0.00

AC:

AN:

60320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.028

Eigen

Benign

-0.17

Eigen_PC

Benign

0.049

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.010

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.69

PhyloP100

6.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.76

REVEL

Benign

0.074

Sift

Benign

0.24

Sift4G

Benign

0.62

Polyphen

0.0010

Vest4

0.41

MutPred

0.17

Gain of disorder (P = 0.0697)

MVP

0.53

MPC

0.32

ClinPred

0.80

GERP RS

5.0

Varity_R

0.085

gMVP

0.16

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over