rs80052257

Variant names:

• chr12-48921403-G-A
• rs80052257
• NM_033124.5:c.1415G>A

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.1415G>A​(p.Arg472His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,613,282 control chromosomes in the GnomAD database, including 313 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. R472C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (168 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (145 hom.)
• Consequence: DRC2 NM_033124.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.991
• Publications: 7 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]

ENSG00000272822 (HGNC:):

FKBP11 (HGNC:18624): (FKBP prolyl isomerase 11) FKBP11 belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. The peptidyl-prolyl isomerase activity of FKBP proteins is inhibited by the immunosuppressant compounds FK506 and rapamycin (Rulten et al., 2006 [PubMed 16596453]).[supplied by OMIM, Mar 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019032955).
• BP6: Variant 12-48921403-G-A is Benign according to our data. Variant chr12-48921403-G-A is described in ClinVar as Benign. ClinVar VariationId is 416602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0826 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.1415G>A	p.Arg472His	missense	Exon 8 of 8	NP_149115.2	Q8IXS2-1
	DRC2	NM_001286957.2		c.986G>A	p.Arg329His	missense	Exon 8 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.1415G>A	p.Arg472His	missense	Exon 8 of 8	ENSP00000312706.4	Q8IXS2-1
	ENSG00000272822	ENST00000398092.4	TSL:3	c.385-17495C>T		intron	N/A	ENSP00000438507.1	F5H423
	CCDC65	ENST00000266984.9	TSL:5	c.1415G>A	p.Arg472His	missense	Exon 8 of 9	ENSP00000266984.5	Q8IXS2-2

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3769 AN: 152000 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.0849

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0245

GnomAD2 exomes AF: 0.00639 AC: 1607 AN: 251382 AF XY: 0.00454

Gnomad AFR exome AF: 0.0870

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00264 AC: 3854 AN: 1461164 Hom.: 145 Cov.: 36 AF XY: 0.00228 AC XY: 1655 AN XY: 726762

African (AFR) AF: 0.0899 AC: 3009 AN: 33462

American (AMR) AF: 0.00514 AC: 230 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5762

European-Non Finnish (NFE) AF: 0.000172 AC: 191 AN: 1111394

Other (OTH) AF: 0.00631 AC: 381 AN: 60358

GnomAD4 genome AF: 0.0248 AC: 3780 AN: 152118 Hom.: 168 Cov.: 32 AF XY: 0.0229 AC XY: 1702 AN XY: 74354

African (AFR) AF: 0.0849 AC: 3522 AN: 41480

American (AMR) AF: 0.0117 AC: 178 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68016

Other (OTH) AF: 0.0242 AC: 51 AN: 2106

Alfa AF: 0.00917 Hom.: 103

Bravo AF: 0.0282

ESP6500AA AF: 0.0810 AC: 357

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00797 AC: 968

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.99
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.042
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.073
MVP		0.055
MPC		0.059
ClinPred		0.0089	T
GERP RS		2.2
Varity_R		0.033
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs80052257; hg19: chr12-49315186; COSMIC: COSV56739985; COSMIC: COSV56739985;