chr2-26414360-T-C

Variant names:

• chr2-26414360-T-C
• rs74936036
• NM_145038.5:c.172T>C

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.172T>C​(p.Tyr58His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,613,834 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. Y58Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (124 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (123 hom.)
• Consequence: DRC1 NM_145038.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.620
• Publications: 8 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 Submitted by: ClinGen, Ambry Genetics, G2P, 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016460717).
• BP6: Variant 2-26414360-T-C is Benign according to our data. Variant chr2-26414360-T-C is described in ClinVar as Benign. ClinVar VariationId is 414288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0741 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.172T>C	p.Tyr58His	missense	Exon 2 of 17	NP_659475.2	Q96MC2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	ENST00000288710.7	TSL:2 MANE Select	c.172T>C	p.Tyr58His	missense	Exon 2 of 17	ENSP00000288710.2	Q96MC2
	DRC1	ENST00000421869.5	TSL:1	n.172T>C		non_coding_transcript_exon	Exon 2 of 8	ENSP00000414375.1	F8WE02
	DRC1	ENST00000868388.1		c.172T>C	p.Tyr58His	missense	Exon 2 of 17	ENSP00000538447.1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3425 AN: 152042 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00593 AC: 1489 AN: 251186 AF XY: 0.00425

Gnomad AFR exome AF: 0.0765

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00249 AC: 3633 AN: 1461674 Hom.: 123 Cov.: 30 AF XY: 0.00218 AC XY: 1587 AN XY: 727150

African (AFR) AF: 0.0805 AC: 2695 AN: 33466

American (AMR) AF: 0.00548 AC: 245 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86218

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.000221 AC: 246 AN: 1111914

Other (OTH) AF: 0.00599 AC: 362 AN: 60386

GnomAD4 genome AF: 0.0225 AC: 3430 AN: 152160 Hom.: 124 Cov.: 32 AF XY: 0.0218 AC XY: 1621 AN XY: 74388

African (AFR) AF: 0.0763 AC: 3166 AN: 41484

American (AMR) AF: 0.0124 AC: 190 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68018

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00759 Hom.: 57

Bravo AF: 0.0257

ESP6500AA AF: 0.0715 AC: 315

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00702 AC: 852

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.00063	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.62
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.010
Sift	Benign	0.52	T
Sift4G	Benign	0.58	T
Polyphen		0.0010	B
Vest4		0.28
MVP		0.12
MPC		0.071
ClinPred		0.0039	T
GERP RS		1.4
Varity_R		0.031
gMVP		0.21
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: rs74936036; hg19: chr2-26637228;