12-48914501-A-G

Variant names:

Variant summary

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

The NM_033124.5(DRC2):c.398A>G(p.His133Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,613,544 control chromosomes in the GnomAD database, including 115,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H133Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.33 ( 9159 hom., cov: 32)

Exomes 𝑓: 0.38 ( 106224 hom. )

Consequence

DRC2
NM_033124.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.33

Publications

34 publications found

Variant links:

Genes affected

DRC2 (HGNC:29937): (coiled-coil domain containing 65) This gene encodes a sperm tail protein that is highly expressed in adult testis, spermatocytes and spermatids. The protein plays a critical role in the assembly of the nexin-dynein regulatory complex. Mutations in this gene result in primary ciliary dyskinesia. [provided by RefSeq, Nov 2013]

DRC2 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 27
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DRC2 links:

ENSG00000272822 (HGNC:):

ENSG00000272822 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=1.7789006E-4).

BP6

Variant 12-48914501-A-G is Benign according to our data. Variant chr12-48914501-A-G is described in ClinVar as Benign. ClinVar VariationId is 402501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033124.5. 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
	DRC2	NM_033124.5	MANE Select	c.398A>G	p.His133Arg	missense	Exon 3 of 8	NP_149115.2
	DRC2	NM_001286957.2		c.-32A>G		5_prime_UTR	Exon 3 of 8	NP_001273886.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCDC65	ENST00000320516.5	TSL:1 MANE Select	c.398A>G	p.His133Arg	missense	Exon 3 of 8	ENSP00000312706.4
ENSG00000272822	ENST00000398092.4	TSL:3	c.385-10593T>C		intron	N/A	ENSP00000438507.1
CCDC65	ENST00000266984.9	TSL:5	c.398A>G	p.His133Arg	missense	Exon 3 of 9	ENSP00000266984.5

Frequencies

GnomAD3 genomes

AF:

0.327

AC:

49763

AN:

151988

Hom.:

9150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.476

Gnomad ASJ

AF:

0.435

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.222

Gnomad FIN

AF:

0.372

Gnomad MID

AF:

0.395

Gnomad NFE

AF:

0.377

Gnomad OTH

AF:

0.361

GnomAD2 exomes

AF:

0.382

AC:

96026

AN:

251288

AF XY:

0.374

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.553

Gnomad ASJ exome

AF:

0.437

Gnomad EAS exome

AF:

0.469

Gnomad FIN exome

AF:

0.383

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.389

GnomAD4 exome

AF:

0.375

AC:

548147

AN:

1461438

Hom.:

106224

Cov.:

AF XY:

0.372

AC XY:

270117

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.155

AC:

5171

AN:

33466

American (AMR)

AF:

0.538

AC:

24060

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

11276

AN:

26128

East Asian (EAS)

AF:

0.477

AC:

18931

AN:

39690

South Asian (SAS)

AF:

0.224

AC:

19311

AN:

86226

European-Finnish (FIN)

AF:

0.387

AC:

20649

AN:

53400

Middle Eastern (MID)

AF:

0.377

AC:

2170

AN:

5762

European-Non Finnish (NFE)

AF:

0.382

AC:

424416

AN:

1111694

Other (OTH)

AF:

0.367

AC:

22163

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

17515

35030

52545

70060

87575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13228

26456

39684

52912

66140

<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:

0.327

AC:

49784

AN:

152106

Hom.:

9159

Cov.:

AF XY:

0.331

AC XY:

24601

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.161

AC:

6664

AN:

41520

American (AMR)

AF:

0.476

AC:

7280

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.435

AC:

1510

AN:

3470

East Asian (EAS)

AF:

0.472

AC:

2435

AN:

5164

South Asian (SAS)

AF:

0.221

AC:

1068

AN:

4826

European-Finnish (FIN)

AF:

0.372

AC:

3934

AN:

10562

Middle Eastern (MID)

AF:

0.394

AC:

115

AN:

292

European-Non Finnish (NFE)

AF:

0.377

AC:

25618

AN:

67976

Other (OTH)

AF:

0.365

AC:

767

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1628

3255

4883

6510

8138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.374

Hom.:

28436

Bravo

AF:

0.338

TwinsUK

AF:

0.374

AC:

1386

ALSPAC

AF:

0.375

AC:

1445

ESP6500AA

AF:

0.161

AC:

711

ESP6500EA

AF:

0.382

AC:

3288

ExAC

AF:

0.370

AC:

44889

Asia WGS

AF:

0.360

AC:

1250

AN:

3478

EpiCase

AF:

0.389

EpiControl

AF:

0.392

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Primary ciliary dyskinesia 27 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.00032

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.26

MetaRNN

Benign

0.00018

MetaSVM

Benign

-0.90

PhyloP100

3.3

PrimateAI

Benign

0.30

PROVEAN

Benign

0.56

REVEL

Benign

0.086

Sift

Benign

0.57

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.018

MPC

0.057

ClinPred

0.0078

GERP RS

0.87

Varity_R

0.026

gMVP

0.031

Mutation Taster

=99/1

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