rs146370108

Variant names:

• chr12-48918910-CAG-C
• rs146370108
• NM_033124.5:c.1026+8_1026+9delAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_033124.5(DRC2):​c.1026+8_1026+9delAG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 1,604,740 control chromosomes in the GnomAD database, including 9,147 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (942 hom., cov: 30)
  • Exomes 𝑓: 0.087 (8205 hom.)
• Consequence: DRC2 NM_033124.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.28
• Publications: 3 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000272822 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-48918910-CAG-C is Benign according to our data. Variant chr12-48918910-CAG-C is described in ClinVar as Benign. ClinVar VariationId is 220953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC2	NM_033124.5	c.1026+8_1026+9delAG		splice_region_variant, intron_variant	Intron 6 of 7	ENST00000320516.5	NP_149115.2
DRC2	NM_001286957.2	c.597+8_597+9delAG		splice_region_variant, intron_variant	Intron 6 of 7		NP_001273886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5	c.1026+8_1026+9delAG		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_033124.5	ENSP00000312706.4
ENSG00000272822	ENST00000398092.4	c.385-15004_385-15003delCT		intron_variant	Intron 4 of 4	3		ENSP00000438507.1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12364 AN: 152014 Hom.: 931 Cov.: 30

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0707

Gnomad OTH AF: 0.0852

GnomAD2 exomes AF: 0.126 AC: 31677 AN: 250664 AF XY: 0.117

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.0759

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0872 AC: 126608 AN: 1452608 Hom.: 8205 AF XY: 0.0860 AC XY: 62193 AN XY: 723196

African (AFR) AF: 0.0128 AC: 427 AN: 33312

American (AMR) AF: 0.328 AC: 14606 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0497 AC: 1296 AN: 26098

East Asian (EAS) AF: 0.266 AC: 10543 AN: 39640

South Asian (SAS) AF: 0.0754 AC: 6492 AN: 86060

European-Finnish (FIN) AF: 0.131 AC: 6970 AN: 53406

Middle Eastern (MID) AF: 0.0709 AC: 408 AN: 5756

European-Non Finnish (NFE) AF: 0.0733 AC: 80926 AN: 1103712

Other (OTH) AF: 0.0823 AC: 4940 AN: 60042

GnomAD4 genome AF: 0.0814 AC: 12391 AN: 152132 Hom.: 942 Cov.: 30 AF XY: 0.0868 AC XY: 6456 AN XY: 74352

African (AFR) AF: 0.0186 AC: 771 AN: 41542

American (AMR) AF: 0.225 AC: 3436 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3468

East Asian (EAS) AF: 0.261 AC: 1349 AN: 5164

South Asian (SAS) AF: 0.0809 AC: 390 AN: 4820

European-Finnish (FIN) AF: 0.120 AC: 1273 AN: 10578

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0707 AC: 4805 AN: 67976

Other (OTH) AF: 0.0914 AC: 193 AN: 2112

Alfa AF: 0.0705 Hom.: 88

Bravo AF: 0.0915

Asia WGS AF: 0.182 AC: 632 AN: 3478

EpiCase AF: 0.0721

EpiControl AF: 0.0729

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -

Primary ciliary dyskinesia 27 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	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: rs146370108; hg19: chr12-49312693; COSMIC: COSV107217371; COSMIC: COSV107217371;