rs1192295

Variant names:

• chr2-84694309-A-G
• rs1192295
• NM_001370.2:c.7353A>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_001370.2(DNAH6):​c.7353A>G​(p.Thr2451Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,552,234 control chromosomes in the GnomAD database, including 4,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1343 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3152 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.139
• Publications: 7 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):

• spermatogenic failure

  Inheritance: AR Classification: STRONG Submitted by: ClinGen
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-84694309-A-G is Benign according to our data. Variant chr2-84694309-A-G is described in ClinVar as Benign. ClinVar VariationId is 402741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.139 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH6	NM_001370.2	MANE Select	c.7353A>G	p.Thr2451Thr	synonymous	Exon 46 of 77	NP_001361.1	Q9C0G6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH6	ENST00000389394.8	TSL:5 MANE Select	c.7353A>G	p.Thr2451Thr	synonymous	Exon 46 of 77	ENSP00000374045.3	Q9C0G6-1
	DNAH6	ENST00000602588.1	TSL:1	n.1434A>G		non_coding_transcript_exon	Exon 10 of 11

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15521 AN: 152206 Hom.: 1342 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.0610

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0812

GnomAD2 exomes AF: 0.0553 AC: 8768 AN: 158578 AF XY: 0.0530

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00128

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0546

Gnomad OTH exome AF: 0.0515

GnomAD4 exome AF: 0.0578 AC: 80911 AN: 1399910 Hom.: 3152 Cov.: 31 AF XY: 0.0573 AC XY: 39574 AN XY: 690446

African (AFR) AF: 0.239 AC: 7539 AN: 31600

American (AMR) AF: 0.0376 AC: 1342 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 484 AN: 25182

East Asian (EAS) AF: 0.000811 AC: 29 AN: 35738

South Asian (SAS) AF: 0.0644 AC: 5099 AN: 79234

European-Finnish (FIN) AF: 0.0386 AC: 1913 AN: 49512

Middle Eastern (MID) AF: 0.0614 AC: 350 AN: 5702

European-Non Finnish (NFE) AF: 0.0560 AC: 60447 AN: 1079064

Other (OTH) AF: 0.0637 AC: 3708 AN: 58170

GnomAD4 genome AF: 0.102 AC: 15544 AN: 152324 Hom.: 1343 Cov.: 33 AF XY: 0.0994 AC XY: 7401 AN XY: 74494

African (AFR) AF: 0.235 AC: 9779 AN: 41552

American (AMR) AF: 0.0592 AC: 906 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5192

South Asian (SAS) AF: 0.0613 AC: 296 AN: 4830

European-Finnish (FIN) AF: 0.0409 AC: 434 AN: 10624

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0556 AC: 3783 AN: 68030

Other (OTH) AF: 0.0803 AC: 170 AN: 2116

Alfa AF: 0.0692 Hom.: 2152

Bravo AF: 0.107

Asia WGS AF: 0.0460 AC: 162 AN: 3478

ClinVar

ClinVar submissions

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	-0.61
CADD	Benign	3.1
DANN	Benign	0.66
PhyloP100		-0.14
Mutation Taster		=93/7	polymorphism (auto)

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: rs1192295; hg19: chr2-84921433;