rs35313480

Variant names:

• chr2-26456494-G-A
• rs35313480
• NM_145038.5:c.2200G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145038.5(DRC1):​c.2200G>A​(p.Val734Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0536 in 1,614,084 control chromosomes in the GnomAD database, including 2,640 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V734V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.042 (182 hom., cov: 33)
  • Exomes 𝑓: 0.055 (2458 hom.)
• Consequence: DRC1 NM_145038.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.19
• Publications: 13 publications found

Genes affected

DRC1 (HGNC:24245): (dynein regulatory complex subunit 1) This gene encodes a central component of the nexin-dynein complex (N-DRC), which regulates the assembly of ciliary dynein. Mutations in this gene can cause ciliary dyskinesia. [provided by RefSeq, Aug 2015]

DRC1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 21

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 80

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021615028).
• BP6: Variant 2-26456494-G-A is Benign according to our data. Variant chr2-26456494-G-A is described in ClinVar as Benign. ClinVar VariationId is 402799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145038.5. 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
	DRC1	NM_145038.5	MANE Select	c.2200G>A	p.Val734Met	missense	Exon 17 of 17	NP_659475.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	ENST00000288710.7	TSL:2 MANE Select	c.2200G>A	p.Val734Met	missense	Exon 17 of 17	ENSP00000288710.2
	DRC1	ENST00000868388.1		c.2125G>A	p.Val709Met	missense	Exon 17 of 17	ENSP00000538447.1
	DRC1	ENST00000941553.1		c.1903G>A	p.Val635Met	missense	Exon 15 of 15	ENSP00000611612.1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6378 AN: 152190 Hom.: 182 Cov.: 33

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0881

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0619

Gnomad OTH AF: 0.0607

GnomAD2 exomes AF: 0.0411 AC: 10326 AN: 251352 AF XY: 0.0423

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.0279

Gnomad ASJ exome AF: 0.0910

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.0600

Gnomad OTH exome AF: 0.0521

GnomAD4 exome AF: 0.0548 AC: 80152 AN: 1461776 Hom.: 2458 Cov.: 31 AF XY: 0.0541 AC XY: 39305 AN XY: 727196

African (AFR) AF: 0.00929 AC: 311 AN: 33480

American (AMR) AF: 0.0300 AC: 1339 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 2336 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0226 AC: 1949 AN: 86246

European-Finnish (FIN) AF: 0.0224 AC: 1198 AN: 53418

Middle Eastern (MID) AF: 0.0562 AC: 324 AN: 5764

European-Non Finnish (NFE) AF: 0.0625 AC: 69475 AN: 1111940

Other (OTH) AF: 0.0533 AC: 3217 AN: 60394

GnomAD4 genome AF: 0.0418 AC: 6374 AN: 152308 Hom.: 182 Cov.: 33 AF XY: 0.0395 AC XY: 2943 AN XY: 74474

African (AFR) AF: 0.0116 AC: 481 AN: 41566

American (AMR) AF: 0.0560 AC: 857 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0881 AC: 306 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4828

European-Finnish (FIN) AF: 0.0210 AC: 223 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0619 AC: 4212 AN: 68018

Other (OTH) AF: 0.0601 AC: 127 AN: 2114

Alfa AF: 0.0546 Hom.: 568

Bravo AF: 0.0437

TwinsUK AF: 0.0663 AC: 246

ALSPAC AF: 0.0542 AC: 209

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.0640 AC: 550

ExAC AF: 0.0406 AC: 4929

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0638

EpiControl AF: 0.0628

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.070
Sift	Benign	0.18	T
Sift4G	Benign	0.19	T
Polyphen		0.063	B
Vest4		0.090
MPC		0.15
ClinPred		0.024	T
GERP RS		4.8
Varity_R		0.082
gMVP		0.19
Mutation Taster		=99/1	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: rs35313480; hg19: chr2-26679362; COSMIC: COSV55503141; COSMIC: COSV55503141;