2-26444747-T-G

Variant names:

• chr2-26444747-T-G
• rs939820
• NM_145038.5:c.1195T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145038.5(DRC1):​c.1195T>G​(p.Trp399Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W399R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: DRC1 NM_145038.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 24 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: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, PanelApp Australia, 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064148515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC1	NM_145038.5	c.1195T>G	p.Trp399Gly	missense_variant	Exon 10 of 17	ENST00000288710.7	NP_659475.2
DRC1	XM_047446339.1	c.175T>G	p.Trp59Gly	missense_variant	Exon 3 of 10		XP_047302295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRC1	ENST00000288710.7	c.1195T>G	p.Trp399Gly	missense_variant	Exon 10 of 17	2	NM_145038.5	ENSP00000288710.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.0010	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.093
MutPred		0.41		Gain of ubiquitination at K397 (P = 0.0737);
MVP		0.12
MPC		0.093
ClinPred		0.10	T
GERP RS		5.5
Varity_R		0.070
gMVP		0.28
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs939820; hg19: chr2-26667615;