17-7727148-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_020877.5(DNAH2):c.255G>A(p.Ala85=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,584,204 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: DNAH2 NM_020877.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.134

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-7727148-G-A is Benign according to our data. Variant chr17-7727148-G-A is described in ClinVar as [Benign]. Clinvar id is 3052762.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.134 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00365 (556/152248) while in subpopulation AFR AF= 0.0125 (521/41536). AF 95% confidence interval is 0.0117. There are 7 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH2	NM_020877.5	c.255G>A	p.Ala85=	synonymous_variant	4/86	ENST00000572933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH2	ENST00000572933.6	c.255G>A	p.Ala85=	synonymous_variant	4/86	2	NM_020877.5	P1
DNAH2	ENST00000570791.5	c.255G>A	p.Ala85=	synonymous_variant	4/14	1
DNAH2	ENST00000389173.6	c.255G>A	p.Ala85=	synonymous_variant	3/85	2		P1

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 551 AN: 152130 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000981 AC: 220 AN: 224156 Hom.: 1 AF XY: 0.000734 AC XY: 90 AN XY: 122580

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000879

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000741

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.000939

GnomAD4 exome AF: 0.000341 AC: 489 AN: 1431956 Hom.: 3 Cov.: 30 AF XY: 0.000292 AC XY: 208 AN XY: 712148

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.000788

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000740

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000245

Gnomad4 OTH exome AF: 0.000658

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152248 Hom.: 7 Cov.: 31 AF XY: 0.00367 AC XY: 273 AN XY: 74444

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00405

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DNAH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.7
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35406368; hg19: chr17-7630466;