12-48921417-G-C

Variant names:

• chr12-48921417-G-C
• rs117927481
• NM_033124.5:c.1429G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033124.5(DRC2):​c.1429G>C​(p.Gly477Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G477S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DRC2 NM_033124.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.897
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05313626).

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.1429G>C	p.Gly477Arg	missense	Exon 8 of 8	NP_149115.2	Q8IXS2-1
	DRC2	NM_001286957.2		c.1000G>C	p.Gly334Arg	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.1429G>C	p.Gly477Arg	missense	Exon 8 of 8	ENSP00000312706.4	Q8IXS2-1
	ENSG00000272822	ENST00000398092.4	TSL:3	c.385-17509C>G		intron	N/A	ENSP00000438507.1	F5H423
	CCDC65	ENST00000943642.1		c.1210G>C	p.Gly404Arg	missense	Exon 7 of 7	ENSP00000613701.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458232 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 724574

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108852

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	10
DANN	Benign	0.91
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.90
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.056
Sift	Benign	0.64	T
Sift4G	Benign	0.83	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.28		Loss of ubiquitination at K479 (P = 0.0213)
MVP		0.030
MPC		0.057
ClinPred		0.14	T
GERP RS		1.0
Varity_R		0.036
gMVP		0.20
Mutation Taster		=95/5	polymorphism

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: rs117927481; hg19: chr12-49315200;