rs143980408

Positions:

• chr2-26448786-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145038.5(DRC1):​c.1492C>G​(p.Leu498Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,198 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0036 (12 hom.)
• Consequence: DRC1 NM_145038.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.966

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=0.0097338855).
• BP6: Variant 2-26448786-C-G is Benign according to our data. Variant chr2-26448786-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 241934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26448786-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00293 (446/152380) while in subpopulation NFE AF= 0.00372 (253/68036). AF 95% confidence interval is 0.00334. There are 2 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRC1	NM_145038.5	c.1492C>G	p.Leu498Val	missense_variant	11/17	ENST00000288710.7	NP_659475.2
DRC1	XM_047446339.1	c.472C>G	p.Leu158Val	missense_variant	4/10		XP_047302295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRC1	ENST00000288710.7	c.1492C>G	p.Leu498Val	missense_variant	11/17	2	NM_145038.5	ENSP00000288710	P1
DRC1	ENST00000439066.2	n.222C>G		non_coding_transcript_exon_variant	2/5	3
DRC1	ENST00000649059.1	c.*455C>G		3_prime_UTR_variant, NMD_transcript_variant	10/16			ENSP00000497543

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152262 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00300 AC: 755 AN: 251442 Hom.: 1 AF XY: 0.00313 AC XY: 426 AN XY: 135910

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00356 AC: 5211 AN: 1461818 Hom.: 12 Cov.: 32 AF XY: 0.00352 AC XY: 2559 AN XY: 727210

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00162

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.00377

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152380 Hom.: 2 Cov.: 34 AF XY: 0.00306 AC XY: 228 AN XY: 74522

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.00372

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00306 Hom.: 2

Bravo AF: 0.00190

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00320 AC: 388

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.012	D
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.30
MVP		0.56
MPC		0.27
ClinPred		0.018	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.45

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: rs143980408; hg19: chr2-26671654;