rs117927481

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-48921417-G-A
• chr12-48921417-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000320516.5(CCDC65):​c.1429G>A​(p.Gly477Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,610,356 control chromosomes in the GnomAD database, including 51 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (46 hom.)
• Consequence: CCDC65 ENST00000320516.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.897
• Publications: 5 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=0.0036070347).
• BP6: Variant 12-48921417-G-A is Benign according to our data. Variant chr12-48921417-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416601.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 = 0.00593 (902/152132) while in subpopulation NFE AF = 0.00947 (644/68008). AF 95% confidence interval is 0.00886. There are 5 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000320516.5. 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.1429G>A	p.Gly477Ser	missense	Exon 8 of 8	NP_149115.2
	DRC2	NM_001286957.2		c.1000G>A	p.Gly334Ser	missense	Exon 8 of 8	NP_001273886.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC65	ENST00000320516.5	TSL:1 MANE Select	c.1429G>A	p.Gly477Ser	missense	Exon 8 of 8	ENSP00000312706.4
	ENSG00000272822	ENST00000398092.4	TSL:3	c.385-17509C>T		intron	N/A	ENSP00000438507.1
	CCDC65	ENST00000266984.9	TSL:5	c.1429G>A	p.Gly477Ser	missense splice_region	Exon 8 of 9	ENSP00000266984.5

Frequencies

GnomAD3 genomes AF: 0.00593 AC: 902 AN: 152024 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00995

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00947

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00611 AC: 1534 AN: 251102 AF XY: 0.00579

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00966

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00730 AC: 10649 AN: 1458224 Hom.: 46 Cov.: 36 AF XY: 0.00710 AC XY: 5141 AN XY: 724568

African (AFR) AF: 0.00102 AC: 34 AN: 33416

American (AMR) AF: 0.00273 AC: 122 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00513 AC: 134 AN: 26110

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

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86208

European-Finnish (FIN) AF: 0.0110 AC: 590 AN: 53394

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5752

European-Non Finnish (NFE) AF: 0.00848 AC: 9401 AN: 1108844

Other (OTH) AF: 0.00579 AC: 349 AN: 60238

GnomAD4 genome AF: 0.00593 AC: 902 AN: 152132 Hom.: 5 Cov.: 32 AF XY: 0.00573 AC XY: 426 AN XY: 74366

African (AFR) AF: 0.00120 AC: 50 AN: 41494

American (AMR) AF: 0.00380 AC: 58 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00995 AC: 105 AN: 10556

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00947 AC: 644 AN: 68008

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00795 Hom.: 22

Bravo AF: 0.00562

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00654 AC: 794

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00942

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Primary ciliary dyskinesia 27 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.81
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.90
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.021
Sift	Benign	0.86	T
Sift4G	Benign	0.66	T
Polyphen		0.0040	B
Vest4		0.12
MVP		0.030
MPC		0.059
ClinPred		0.0052	T
GERP RS		1.0
Varity_R		0.034
gMVP		0.23
Mutation Taster		=98/2	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; COSMIC: COSV107217359; COSMIC: COSV107217359;