rs748848510

Variant names:

• chr12-48920970-T-C
• rs748848510
• NM_033124.5:c.1067T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033124.5(DRC2):​c.1067T>C​(p.Phe356Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: DRC2 NM_033124.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.06
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048568875).

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.1067T>C	p.Phe356Ser	missense	Exon 7 of 8	NP_149115.2	Q8IXS2-1
	DRC2	NM_001286957.2		c.638T>C	p.Phe213Ser	missense	Exon 7 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.1067T>C	p.Phe356Ser	missense	Exon 7 of 8	ENSP00000312706.4	Q8IXS2-1
	ENSG00000272822	ENST00000398092.4	TSL:3	c.385-17062A>G		intron	N/A	ENSP00000438507.1	F5H423
	CCDC65	ENST00000266984.9	TSL:5	c.1067T>C	p.Phe356Ser	missense	Exon 7 of 9	ENSP00000266984.5	Q8IXS2-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 250754 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.000986 AC: 44 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111882

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000123 AC: 15

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Primary ciliary dyskinesia 27 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.00066
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.30	B
Vest4		0.53
MutPred		0.49		Gain of disorder (P = 0.0047)
MVP		0.081
MPC		0.14
ClinPred		0.14	T
GERP RS		2.9
Varity_R		0.28
gMVP		0.45
Mutation Taster		=85/15	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: rs748848510; hg19: chr12-49314753;