rs754273

Variant names:

• chr2-84796430-A-G
• rs754273
• NM_001370.2:c.11359+5A>G

Variant summary

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

The NM_001370.2(DNAH6):​c.11359+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,498,844 control chromosomes in the GnomAD database, including 23,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4611 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19269 hom.)
• Consequence: DNAH6 NM_001370.2 splice_region, intron
• Scores: Splicing: ADA: 0.0002191
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.310
• Publications: 10 publications found

Genes affected

DNAH6 (HGNC:2951): (dynein axonemal heavy chain 6) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Mutations in this gene may cause primary ciliary dyskinesia (PCD) as well as heterotaxy. [provided by RefSeq, Jun 2016]

DNAH6 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-84796430-A-G is Benign according to our data. Variant chr2-84796430-A-G is described in ClinVar as Benign. ClinVar VariationId is 402745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370.2. 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
	DNAH6	NM_001370.2	MANE Select	c.11359+5A>G		splice_region intron	N/A	NP_001361.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH6	ENST00000389394.8	TSL:5 MANE Select	c.11359+5A>G		splice_region intron	N/A	ENSP00000374045.3

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34190 AN: 151944 Hom.: 4587 Cov.: 32

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.224

GnomAD2 exomes AF: 0.174 AC: 22643 AN: 130108 AF XY: 0.169

Gnomad AFR exome AF: 0.402

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.162 AC: 218027 AN: 1346782 Hom.: 19269 Cov.: 26 AF XY: 0.162 AC XY: 107328 AN XY: 662922

African (AFR) AF: 0.404 AC: 11779 AN: 29154

American (AMR) AF: 0.205 AC: 5811 AN: 28296

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4299 AN: 23828

East Asian (EAS) AF: 0.128 AC: 4431 AN: 34752

South Asian (SAS) AF: 0.148 AC: 10438 AN: 70574

European-Finnish (FIN) AF: 0.152 AC: 7397 AN: 48540

Middle Eastern (MID) AF: 0.215 AC: 1194 AN: 5544

European-Non Finnish (NFE) AF: 0.155 AC: 163120 AN: 1050392

Other (OTH) AF: 0.172 AC: 9558 AN: 55702

GnomAD4 genome AF: 0.225 AC: 34259 AN: 152062 Hom.: 4611 Cov.: 32 AF XY: 0.222 AC XY: 16545 AN XY: 74362

African (AFR) AF: 0.395 AC: 16377 AN: 41440

American (AMR) AF: 0.188 AC: 2870 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3472

East Asian (EAS) AF: 0.106 AC: 551 AN: 5178

South Asian (SAS) AF: 0.140 AC: 673 AN: 4820

European-Finnish (FIN) AF: 0.157 AC: 1659 AN: 10590

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10664 AN: 67974

Other (OTH) AF: 0.224 AC: 473 AN: 2114

Alfa AF: 0.180 Hom.: 8006

Bravo AF: 0.236

Asia WGS AF: 0.155 AC: 541 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	DNAH6-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.3
DANN	Benign	0.53
PhyloP100		-0.31
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.062
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: rs754273; hg19: chr2-85023554; COSMIC: COSV52875853;