rs117035657

Variant names:

• chr17-7733179-G-A
• rs117035657
• NM_020877.5:c.492G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020877.5(DNAH2):​c.492G>A​(p.Arg164Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,614,168 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (10 hom., cov: 31)
  • Exomes 𝑓: 0.011 (125 hom.)
• Consequence: DNAH2 NM_020877.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0810
• Publications: 5 publications found

Genes affected

DNAH2 (HGNC:2948): (dynein axonemal heavy chain 2) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. The axonemal dyneins, found in cilia and flagella, are components of the outer and inner dynein arms attached to the peripheral microtubule doublets. DNAH2 is an axonemal inner arm dynein heavy chain (Chapelin et al., 1997 [PubMed 9256245]).[supplied by OMIM, Mar 2008]

DNAH2 Gene-Disease associations (from GenCC):

• spermatogenic failure 45

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-7733179-G-A is Benign according to our data. Variant chr17-7733179-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 402716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.081 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00843 (1284/152286) while in subpopulation NFE AF = 0.0127 (863/68014). AF 95% confidence interval is 0.012. There are 10 homozygotes in GnomAd4. There are 609 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020877.5. 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
	DNAH2	NM_020877.5	MANE Select	c.492G>A	p.Arg164Arg	synonymous	Exon 5 of 86	NP_065928.2	Q9P225-1
	DNAH2	NM_001303270.2		c.492G>A	p.Arg164Arg	synonymous	Exon 5 of 14	NP_001290199.1	Q9P225-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH2	ENST00000572933.6	TSL:2 MANE Select	c.492G>A	p.Arg164Arg	synonymous	Exon 5 of 86	ENSP00000458355.1	Q9P225-1
	DNAH2	ENST00000570791.5	TSL:1	c.492G>A	p.Arg164Arg	synonymous	Exon 5 of 14	ENSP00000460245.1	Q9P225-3
	DNAH2	ENST00000389173.6	TSL:2	c.492G>A	p.Arg164Arg	synonymous	Exon 4 of 85	ENSP00000373825.2	Q9P225-1

Frequencies

GnomAD3 genomes AF: 0.00844 AC: 1285 AN: 152168 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0103 AC: 2599 AN: 251448 AF XY: 0.0100

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.0112 AC: 16367 AN: 1461882 Hom.: 125 Cov.: 31 AF XY: 0.0107 AC XY: 7807 AN XY: 727244

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00389 AC: 174 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 83 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.0220 AC: 1177 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0129 AC: 14316 AN: 1112006

Other (OTH) AF: 0.00932 AC: 563 AN: 60396

GnomAD4 genome AF: 0.00843 AC: 1284 AN: 152286 Hom.: 10 Cov.: 31 AF XY: 0.00818 AC XY: 609 AN XY: 74472

African (AFR) AF: 0.00212 AC: 88 AN: 41574

American (AMR) AF: 0.00713 AC: 109 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 863 AN: 68014

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00963 Hom.: 6

Bravo AF: 0.00716

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0107

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	DNAH2-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.1
DANN	Benign	0.58
PhyloP100		-0.081
Mutation Taster		=100/0	polymorphism

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: rs117035657; hg19: chr17-7636497; COSMIC: COSV50019961;