chr12-48918898-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033124.5(DRC2):c.1021G>T(p.Asp341Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,610,524 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D341G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0081 ( 7 hom., cov: 31)

Exomes 𝑓: 0.012 ( 117 hom. )

Consequence

DRC2
NM_033124.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.610

Publications

7 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=0.0040610135).

BP6

Variant 12-48918898-G-T is Benign according to our data. Variant chr12-48918898-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00814 (1224/150326) while in subpopulation NFE AF = 0.0125 (844/67702). AF 95% confidence interval is 0.0118. There are 7 homozygotes in GnomAd4. There are 580 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC2	NM_033124.5 link	c.1021G>T	p.Asp341Tyr	missense_variant	Exon 6 of 8	ENST00000320516.5	NP_149115.2	Q8IXS2-1
DRC2	NM_001286957.2 link	c.592G>T	p.Asp198Tyr	missense_variant	Exon 6 of 8		NP_001273886.1	B4DXQ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5 link	c.1021G>T	p.Asp341Tyr	missense_variant	Exon 6 of 8	1	NM_033124.5	ENSP00000312706.4		Q8IXS2-1
ENSG00000272822	ENST00000398092.4 link	c.385-14990C>A		intron_variant	Intron 4 of 4	3		ENSP00000438507.1		F5H423

Frequencies

GnomAD3 genomes

AF:

0.00815

AC:

1225

AN:

150226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00254

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.00293

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.000205

Gnomad SAS

AF:

0.00631

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0125

Gnomad OTH

AF:

0.00870

GnomAD2 exomes

AF:

0.00752

AC:

1887

AN:

251054

AF XY:

0.00780

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00261

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00467

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.0117

AC:

17033

AN:

1460198

Hom.:

117

Cov.:

AF XY:

0.0115

AC XY:

8355

AN XY:

726540

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

33440

American (AMR)

AF:

0.00286

AC:

128

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

264

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00653

AC:

563

AN:

86210

European-Finnish (FIN)

AF:

0.00509

AC:

272

AN:

53416

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0136

AC:

15151

AN:

1110492

Other (OTH)

AF:

0.00936

AC:

565

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

859

1718

2578

3437

4296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.00814

AC:

1224

AN:

150326

Hom.:

Cov.:

AF XY:

0.00790

AC XY:

580

AN XY:

73372

show subpopulations

African (AFR)

AF:

0.00253

AC:

105

AN:

41470

American (AMR)

AF:

0.00292

AC:

AN:

14368

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3454

East Asian (EAS)

AF:

0.000206

AC:

AN:

4866

South Asian (SAS)

AF:

0.00632

AC:

AN:

4748

European-Finnish (FIN)

AF:

0.00508

AC:

AN:

10436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0125

AC:

844

AN:

67702

Other (OTH)

AF:

0.00866

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0109

Hom.:

Bravo

AF:

0.00798

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0149

AC:

128

ExAC

AF:

0.00732

AC:

889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 27

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 04, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DRC2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

.;.;T

Eigen

Benign

-0.089

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0041

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.61

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Benign

0.065

Sift

Uncertain

0.020

D;D;D

Sift4G

Uncertain

0.019

D;D;D

Polyphen

0.95

.;.;P

Vest4

0.38

MVP

0.048

MPC

0.24

ClinPred

0.017

GERP RS

3.8

Varity_R

0.34

gMVP

0.26

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over