chr12-48921211-A-G

Variant names:

• chr12-48921211-A-G
• rs4760600
• NM_033124.5:c.1223A>G

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.1223A>G​(p.Tyr408Cys) variant causes a missense change. The variant allele was found at a frequency of 0.37 in 1,613,700 control chromosomes in the GnomAD database, including 115,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9105 hom., cov: 31)
  • Exomes 𝑓: 0.37 (106109 hom.)
• Consequence: DRC2 NM_033124.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.97
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031661987).
• BP6: Variant 12-48921211-A-G is Benign according to our data. Variant chr12-48921211-A-G is described in ClinVar as Benign. ClinVar VariationId is 402504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC2	NM_033124.5	c.1223A>G	p.Tyr408Cys	missense_variant	Exon 8 of 8	ENST00000320516.5	NP_149115.2
DRC2	NM_001286957.2	c.794A>G	p.Tyr265Cys	missense_variant	Exon 8 of 8		NP_001273886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5	c.1223A>G	p.Tyr408Cys	missense_variant	Exon 8 of 8	1	NM_033124.5	ENSP00000312706.4
ENSG00000272822	ENST00000398092.4	c.385-17303T>C		intron_variant	Intron 4 of 4	3		ENSP00000438507.1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49528 AN: 151948 Hom.: 9098 Cov.: 31

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.357

GnomAD2 exomes AF: 0.382 AC: 95798 AN: 251020 AF XY: 0.373

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.466

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.375 AC: 547957 AN: 1461636 Hom.: 106109 Cov.: 49 AF XY: 0.371 AC XY: 270029 AN XY: 727120

African (AFR) AF: 0.151 AC: 5054 AN: 33480

American (AMR) AF: 0.538 AC: 24057 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 11278 AN: 26134

East Asian (EAS) AF: 0.474 AC: 18814 AN: 39700

South Asian (SAS) AF: 0.224 AC: 19325 AN: 86256

European-Finnish (FIN) AF: 0.387 AC: 20642 AN: 53392

Middle Eastern (MID) AF: 0.377 AC: 2174 AN: 5768

European-Non Finnish (NFE) AF: 0.382 AC: 424507 AN: 1111834

Other (OTH) AF: 0.366 AC: 22106 AN: 60384

GnomAD4 genome AF: 0.326 AC: 49545 AN: 152064 Hom.: 9105 Cov.: 31 AF XY: 0.329 AC XY: 24482 AN XY: 74322

African (AFR) AF: 0.157 AC: 6515 AN: 41518

American (AMR) AF: 0.474 AC: 7239 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1509 AN: 3470

East Asian (EAS) AF: 0.465 AC: 2401 AN: 5158

South Asian (SAS) AF: 0.221 AC: 1065 AN: 4820

European-Finnish (FIN) AF: 0.373 AC: 3933 AN: 10558

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25614 AN: 67960

Other (OTH) AF: 0.359 AC: 757 AN: 2106

Alfa AF: 0.374 Hom.: 53302

Bravo AF: 0.337

TwinsUK AF: 0.374 AC: 1386

ALSPAC AF: 0.375 AC: 1444

ESP6500AA AF: 0.158 AC: 695

ESP6500EA AF: 0.382 AC: 3287

ExAC AF: 0.369 AC: 44788

Asia WGS AF: 0.358 AC: 1243 AN: 3478

EpiCase AF: 0.389

EpiControl AF: 0.392

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 27 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-0.93	T
PhyloP100		4.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.26
MPC		0.36
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.62
gMVP		0.72
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4760600; hg19: chr12-49314994; COSMIC: COSV56739607; COSMIC: COSV56739607;