rs78877829

Variant names:

• chr12-48918757-C-T
• rs78877829
• NM_033124.5:c.880C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033124.5(DRC2):​c.880C>T​(p.Arg294Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0513 in 1,613,972 control chromosomes in the GnomAD database, including 2,609 homozygotes. In-silico tool predicts 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. R294H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.043 (209 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2400 hom.)
• Consequence: DRC2 NM_033124.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.83
• Publications: 11 publications found

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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000272822 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017585754).
• BP6: Variant 12-48918757-C-T is Benign according to our data. Variant chr12-48918757-C-T is described in ClinVar as Benign. ClinVar VariationId is 262221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0598 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC2	NM_033124.5	MANE Select	c.880C>T	p.Arg294Cys	missense	Exon 6 of 8	NP_149115.2	Q8IXS2-1
	DRC2	NM_001286957.2		c.451C>T	p.Arg151Cys	missense	Exon 6 of 8	NP_001273886.1	B4DXQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC65	ENST00000320516.5	TSL:1 MANE Select	c.880C>T	p.Arg294Cys	missense	Exon 6 of 8	ENSP00000312706.4	Q8IXS2-1
	ENSG00000272822	ENST00000398092.4	TSL:3	c.385-14849G>A		intron	N/A	ENSP00000438507.1	F5H423
	CCDC65	ENST00000266984.9	TSL:5	c.880C>T	p.Arg294Cys	missense	Exon 6 of 9	ENSP00000266984.5	Q8IXS2-2

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6513 AN: 152024 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0613

Gnomad OTH AF: 0.0340

GnomAD2 exomes AF: 0.0415 AC: 10442 AN: 251482 AF XY: 0.0419

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0995

Gnomad NFE exome AF: 0.0590

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0522 AC: 76358 AN: 1461830 Hom.: 2400 Cov.: 33 AF XY: 0.0511 AC XY: 37157 AN XY: 727222

African (AFR) AF: 0.00738 AC: 247 AN: 33480

American (AMR) AF: 0.0196 AC: 875 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 514 AN: 26136

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39700

South Asian (SAS) AF: 0.0121 AC: 1045 AN: 86258

European-Finnish (FIN) AF: 0.0981 AC: 5238 AN: 53420

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5760

European-Non Finnish (NFE) AF: 0.0591 AC: 65673 AN: 1111962

Other (OTH) AF: 0.0448 AC: 2708 AN: 60390

GnomAD4 genome AF: 0.0428 AC: 6511 AN: 152142 Hom.: 209 Cov.: 32 AF XY: 0.0446 AC XY: 3320 AN XY: 74364

African (AFR) AF: 0.0105 AC: 435 AN: 41494

American (AMR) AF: 0.0332 AC: 507 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4812

European-Finnish (FIN) AF: 0.109 AC: 1154 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0613 AC: 4171 AN: 67988

Other (OTH) AF: 0.0336 AC: 71 AN: 2110

Alfa AF: 0.0506 Hom.: 846

Bravo AF: 0.0346

TwinsUK AF: 0.0591 AC: 219

ALSPAC AF: 0.0607 AC: 234

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0555 AC: 477

ExAC AF: 0.0413 AC: 5008

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0534

EpiControl AF: 0.0520

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia 27 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.89	T
PhyloP100		2.8
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.26
MPC		0.37
ClinPred		0.026	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.31
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78877829; hg19: chr12-49312540; COSMIC: COSV56740449; COSMIC: COSV56740449;