rs1553345147

Variant names:

• chr2-26455135-G-A
• rs1553345147
• NM_145038.5:c.2068G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145038.5(DRC1):​c.2068G>A​(p.Val690Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V690A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DRC1 NM_145038.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.331
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08667478).

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.2068G>A	p.Val690Ile	missense	Exon 16 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.2068G>A	p.Val690Ile	missense	Exon 16 of 17	ENSP00000288710.2	Q96MC2
	DRC1	ENST00000868388.1		c.1993G>A	p.Val665Ile	missense	Exon 16 of 17	ENSP00000538447.1
	DRC1	ENST00000941553.1		c.1771G>A	p.Val591Ile	missense	Exon 14 of 15	ENSP00000611612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.5
DANN	Benign	0.91
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.33
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.028
Sift	Benign	0.55	T
Sift4G	Benign	0.30	T
Polyphen		0.039	B
Vest4		0.096
MutPred		0.43		Gain of methylation at K686 (P = 0.1105)
MVP		0.23
MPC		0.057
ClinPred		0.085	T
GERP RS		0.51
Varity_R		0.041
gMVP		0.19
Mutation Taster		=93/7	polymorphism

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: rs1553345147; hg19: chr2-26678003;