2-26424335-T-G

Variant names:

• chr2-26424335-T-G
• rs139583194
• NM_145038.5:c.421T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_145038.5(DRC1):​c.421T>G​(p.Trp141Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000399 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: DRC1 NM_145038.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.01
• Publications: 4 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: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000415 (606/1461884) while in subpopulation SAS AF = 0.000696 (60/86256). AF 95% confidence interval is 0.000554. There are 0 homozygotes in GnomAdExome4. There are 291 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	NM_145038.5	MANE Select	c.421T>G	p.Trp141Gly	missense	Exon 4 of 17	NP_659475.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	ENST00000288710.7	TSL:2 MANE Select	c.421T>G	p.Trp141Gly	missense	Exon 4 of 17	ENSP00000288710.2
	DRC1	ENST00000421869.5	TSL:1	n.356+2935T>G		intron	N/A	ENSP00000414375.1
	DRC1	ENST00000868388.1		c.421T>G	p.Trp141Gly	missense	Exon 4 of 17	ENSP00000538447.1

Frequencies

GnomAD3 genomes AF: 0.000251 AC: 38 AN: 151340 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.0000955

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000239 AC: 60 AN: 251384 AF XY: 0.000309

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000415 AC: 606 AN: 1461884 Hom.: 0 Cov.: 30 AF XY: 0.000400 AC XY: 291 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86256

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000455 AC: 506 AN: 1112012

Other (OTH) AF: 0.000513 AC: 31 AN: 60396

GnomAD4 genome AF: 0.000251 AC: 38 AN: 151458 Hom.: 0 Cov.: 31 AF XY: 0.000230 AC XY: 17 AN XY: 73998

African (AFR) AF: 0.0000970 AC: 4 AN: 41246

American (AMR) AF: 0.000395 AC: 6 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4786

European-Finnish (FIN) AF: 0.0000955 AC: 1 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000354 AC: 24 AN: 67874

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.000301 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia 21 (2)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.089	T
Polyphen		1.0	D
Vest4		0.92
MVP		0.62
MPC		0.47
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.67
Mutation Taster		=38/62	disease causing

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: rs139583194; hg19: chr2-26647203;