rs35313480

chr2-26456494-G-A

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.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. 11/19 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:3
• Conservation: PhyloP100: 2.19

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=0.0021615028).
• BP6: Variant 2-26456494-G-A is Benign according to our data. Variant chr2-26456494-G-A is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRC1	NM_145038.5	c.2200G>A	p.Val734Met	missense_variant	17/17	ENST00000288710.7
DRC1	XM_047446339.1	c.1180G>A	p.Val394Met	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRC1	ENST00000288710.7	c.2200G>A	p.Val734Met	missense_variant	17/17	2	NM_145038.5	P1
DRC1	ENST00000649059.1	c.*1163G>A		3_prime_UTR_variant, NMD_transcript_variant	16/16

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

GnomAD3 exomes AF: 0.0411 AC: 10326 AN: 251352 Hom.: 291 AF XY: 0.0423 AC XY: 5753 AN XY: 135852

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 SAS exome AF: 0.0224

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

Gnomad4 AFR exome AF: 0.00929

Gnomad4 AMR exome AF: 0.0300

Gnomad4 ASJ exome AF: 0.0894

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0226

Gnomad4 FIN exome AF: 0.0224

Gnomad4 NFE exome AF: 0.0625

Gnomad4 OTH exome AF: 0.0533

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

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.0560

Gnomad4 ASJ AF: 0.0881

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.0210

Gnomad4 NFE AF: 0.0619

Gnomad4 OTH AF: 0.0601

Alfa AF: 0.0575 Hom.: 432

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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: rs35313480; hg19: chr2-26679362; COSMIC: COSV55503141; COSMIC: COSV55503141;