chr2-26448676-A-G

Variant names:

• chr2-26448676-A-G
• rs4072407
• NM_145038.5:c.1397-15A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145038.5(DRC1):​c.1397-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 1,612,870 control chromosomes in the GnomAD database, including 496,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (37103 hom., cov: 33)
  • Exomes 𝑓: 0.78 (459891 hom.)
• Consequence: DRC1 NM_145038.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.30
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 2-26448676-A-G is Benign according to our data. Variant chr2-26448676-A-G is described in ClinVar as Benign. ClinVar VariationId is 262565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.82 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	NM_145038.5	MANE Select	c.1397-15A>G		intron	N/A	NP_659475.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	ENST00000288710.7	TSL:2 MANE Select	c.1397-15A>G		intron	N/A	ENSP00000288710.2
	DRC1	ENST00000439066.2	TSL:3	n.127-15A>G		intron	N/A
	DRC1	ENST00000649059.1		n.*360-15A>G		intron	N/A	ENSP00000497543.1

Frequencies

GnomAD3 genomes AF: 0.664 AC: 101014 AN: 152044 Hom.: 37097 Cov.: 33

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.872

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.904

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.825

Gnomad OTH AF: 0.695

GnomAD2 exomes AF: 0.714 AC: 179396 AN: 251128 AF XY: 0.733

Gnomad AFR exome AF: 0.357

Gnomad AMR exome AF: 0.565

Gnomad ASJ exome AF: 0.816

Gnomad EAS exome AF: 0.266

Gnomad FIN exome AF: 0.903

Gnomad NFE exome AF: 0.830

Gnomad OTH exome AF: 0.768

GnomAD4 exome AF: 0.783 AC: 1143533 AN: 1460708 Hom.: 459891 Cov.: 35 AF XY: 0.784 AC XY: 570023 AN XY: 726662

African (AFR) AF: 0.354 AC: 11842 AN: 33438

American (AMR) AF: 0.576 AC: 25736 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 21105 AN: 26134

East Asian (EAS) AF: 0.240 AC: 9544 AN: 39686

South Asian (SAS) AF: 0.735 AC: 63362 AN: 86230

European-Finnish (FIN) AF: 0.897 AC: 47929 AN: 53412

Middle Eastern (MID) AF: 0.739 AC: 4250 AN: 5752

European-Non Finnish (NFE) AF: 0.823 AC: 914477 AN: 1111022

Other (OTH) AF: 0.751 AC: 45288 AN: 60336

GnomAD4 genome AF: 0.664 AC: 101047 AN: 152162 Hom.: 37103 Cov.: 33 AF XY: 0.666 AC XY: 49579 AN XY: 74406

African (AFR) AF: 0.374 AC: 15527 AN: 41480

American (AMR) AF: 0.628 AC: 9607 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 2846 AN: 3468

East Asian (EAS) AF: 0.264 AC: 1364 AN: 5170

South Asian (SAS) AF: 0.722 AC: 3480 AN: 4818

European-Finnish (FIN) AF: 0.904 AC: 9591 AN: 10606

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.826 AC: 56148 AN: 68014

Other (OTH) AF: 0.697 AC: 1473 AN: 2114

Alfa AF: 0.769 Hom.: 177535

Bravo AF: 0.625

Asia WGS AF: 0.573 AC: 1989 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	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	-1.0
CADD	Benign	0.0060
DANN	Benign	0.26
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4072407; hg19: chr2-26671544; COSMIC: COSV56531656; COSMIC: COSV56531656;