2-26424409-T-G

Variant names:

• chr2-26424409-T-G
• rs7423300
• NM_145038.5:c.495T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_145038.5(DRC1):​c.495T>G​(p.Ala165Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.842 in 1,613,406 control chromosomes in the GnomAD database, including 585,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A165A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.76 (46068 hom., cov: 29)
  • Exomes 𝑓: 0.85 (539444 hom.)
• Consequence: DRC1 NM_145038.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.06
• Publications: 17 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-26424409-T-G is Benign according to our data. Variant chr2-26424409-T-G is described in ClinVar as Benign. ClinVar VariationId is 262566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

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.495T>G	p.Ala165Ala	synonymous	Exon 4 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.495T>G	p.Ala165Ala	synonymous	Exon 4 of 17	ENSP00000288710.2	Q96MC2
	DRC1	ENST00000421869.5	TSL:1	n.356+3009T>G		intron	N/A	ENSP00000414375.1	F8WE02
	DRC1	ENST00000868388.1		c.495T>G	p.Ala165Ala	synonymous	Exon 4 of 17	ENSP00000538447.1

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115199 AN: 151614 Hom.: 46066 Cov.: 29

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.771

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.890

Gnomad OTH AF: 0.781

GnomAD2 exomes AF: 0.774 AC: 194160 AN: 250974 AF XY: 0.790

Gnomad AFR exome AF: 0.554

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.858

Gnomad EAS exome AF: 0.305

Gnomad FIN exome AF: 0.929

Gnomad NFE exome AF: 0.892

Gnomad OTH exome AF: 0.826

GnomAD4 exome AF: 0.850 AC: 1243105 AN: 1461676 Hom.: 539444 Cov.: 61 AF XY: 0.851 AC XY: 618458 AN XY: 727130

African (AFR) AF: 0.555 AC: 18586 AN: 33474

American (AMR) AF: 0.614 AC: 27473 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 22257 AN: 26136

East Asian (EAS) AF: 0.306 AC: 12160 AN: 39696

South Asian (SAS) AF: 0.780 AC: 67294 AN: 86238

European-Finnish (FIN) AF: 0.926 AC: 49454 AN: 53408

Middle Eastern (MID) AF: 0.801 AC: 4520 AN: 5642

European-Non Finnish (NFE) AF: 0.892 AC: 991707 AN: 1111986

Other (OTH) AF: 0.822 AC: 49654 AN: 60374

GnomAD4 genome AF: 0.759 AC: 115237 AN: 151730 Hom.: 46068 Cov.: 29 AF XY: 0.757 AC XY: 56137 AN XY: 74154

African (AFR) AF: 0.567 AC: 23393 AN: 41272

American (AMR) AF: 0.694 AC: 10574 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2981 AN: 3470

East Asian (EAS) AF: 0.310 AC: 1588 AN: 5128

South Asian (SAS) AF: 0.769 AC: 3707 AN: 4818

European-Finnish (FIN) AF: 0.929 AC: 9791 AN: 10536

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.890 AC: 60496 AN: 67972

Other (OTH) AF: 0.782 AC: 1645 AN: 2104

Alfa AF: 0.825 Hom.: 40455

Bravo AF: 0.727

Asia WGS AF: 0.628 AC: 2182 AN: 3478

EpiCase AF: 0.886

EpiControl AF: 0.888

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Primary ciliary dyskinesia (1)
-	-	1	Primary ciliary dyskinesia 21 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.055
DANN	Benign	0.39
PhyloP100		-2.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7423300; hg19: chr2-26647277; COSMIC: COSV56529128;