rs74936036

chr2-26414360-T-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:3
• Conservation: PhyloP100: 0.620

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRC1	NM_145038.5	c.172T>C	p.Tyr58His	missense_variant	2/17	ENST00000288710.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRC1	ENST00000288710.7	c.172T>C	p.Tyr58His	missense_variant	2/17	2	NM_145038.5	P1
DRC1	ENST00000421869.5	c.172T>C	p.Tyr58His	missense_variant, NMD_transcript_variant	2/8	1
DRC1	ENST00000649059.1	c.160T>C	p.Tyr54His	missense_variant, NMD_transcript_variant	2/16

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

GnomAD3 exomes AF: 0.00593 AC: 1489 AN: 251186 Hom.: 60 AF XY: 0.00425 AC XY: 577 AN XY: 135762

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 SAS exome AF: 0.000164

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

Gnomad4 AFR exome AF: 0.0805

Gnomad4 AMR exome AF: 0.00548

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00599

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

Gnomad4 AFR AF: 0.0763

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00417 Hom.: 26

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.99	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs74936036; hg19: chr2-26637228;