Genetic Variant NM_019044.5:c.683C>T (chr2-117975255-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_019044.5(CCDC93):c.683C>T(p.Pro228Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0717 in 1,612,948 control chromosomes in the GnomAD database, including 4,685 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 286 hom., cov: 32)

Exomes 𝑓: 0.074 ( 4399 hom. )

Consequence

CCDC93
NM_019044.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.65

Publications

24 publications found

Variant links:

Genes affected

CCDC93 (HGNC:25611): (coiled-coil domain containing 93) Involved in Golgi to plasma membrane transport and endocytic recycling. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

CCDC93 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017846525).

BP6

Variant 2-117975255-G-A is Benign according to our data. Variant chr2-117975255-G-A is described in ClinVar as Benign. ClinVar VariationId is 1271261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019044.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC93	NM_019044.5	MANE Select	c.683C>T	p.Pro228Leu	missense	Exon 9 of 24	NP_061917.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC93	ENST00000376300.7	TSL:1 MANE Select	c.683C>T	p.Pro228Leu	missense	Exon 9 of 24	ENSP00000365477.2
CCDC93	ENST00000884940.1		c.683C>T	p.Pro228Leu	missense	Exon 9 of 25	ENSP00000554999.1
CCDC93	ENST00000951763.1		c.701C>T	p.Pro234Leu	missense	Exon 10 of 25	ENSP00000621822.1

Frequencies

GnomAD3 genomes

AF:

0.0529

AC:

8050

AN:

152158

Hom.:

287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0129

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0352

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0537

Gnomad FIN

AF:

0.0697

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0824

Gnomad OTH

AF:

0.0465

GnomAD2 exomes

AF:

0.0564

AC:

14154

AN:

250852

AF XY:

0.0587

show subpopulations

Gnomad AFR exome

AF:

0.0118

Gnomad AMR exome

AF:

0.0298

Gnomad ASJ exome

AF:

0.0629

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0710

Gnomad NFE exome

AF:

0.0754

Gnomad OTH exome

AF:

0.0656

GnomAD4 exome

AF:

0.0736

AC:

107551

AN:

1460672

Hom.:

4399

Cov.:

AF XY:

0.0737

AC XY:

53592

AN XY:

726716

show subpopulations

African (AFR)

AF:

0.0116

AC:

387

AN:

33474

American (AMR)

AF:

0.0307

AC:

1374

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0608

AC:

1588

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0611

AC:

5268

AN:

86252

European-Finnish (FIN)

AF:

0.0740

AC:

3907

AN:

52798

Middle Eastern (MID)

AF:

0.0702

AC:

404

AN:

5758

European-Non Finnish (NFE)

AF:

0.0813

AC:

90333

AN:

1111468

Other (OTH)

AF:

0.0710

AC:

4287

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

4592

9184

13777

18369

22961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3254

6508

9762

13016

16270

<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

AF:

0.0528

AC:

8043

AN:

152276

Hom.:

286

Cov.:

AF XY:

0.0514

AC XY:

3829

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0128

AC:

534

AN:

41580

American (AMR)

AF:

0.0351

AC:

537

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

197

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0535

AC:

258

AN:

4818

European-Finnish (FIN)

AF:

0.0697

AC:

740

AN:

10610

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0824

AC:

5601

AN:

68008

Other (OTH)

AF:

0.0460

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

391

782

1174

1565

1956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0700

Hom.:

1265

Bravo

AF:

0.0481

TwinsUK

AF:

0.0871

AC:

323

ALSPAC

AF:

0.0771

AC:

297

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.0809

AC:

696

ExAC

AF:

0.0571

AC:

6936

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.0809

EpiControl

AF:

0.0759

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.0032

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

4.6

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.89

REVEL

Benign

0.064

Sift

Benign

0.062

Sift4G

Benign

0.30

Polyphen

0.0070

Vest4

0.10

MPC

0.29

ClinPred

0.013

GERP RS

5.2

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.1

Varity_R

0.059

gMVP

0.27

Mutation Taster

=94/6

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over