rs117465420

Positions:

• chr17-7831158-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_020877.5(DNAH2):​c.12303A>T​(p.Leu4101Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0235 in 1,614,068 control chromosomes in the GnomAD database, including 618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (62 hom., cov: 32)
  • Exomes 𝑓: 0.024 (556 hom.)
• Consequence: DNAH2 NM_020877.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.05

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNAH2. . Gene score misZ 1.883 (greater than the threshold 3.09). Trascript score misZ 4.8003 (greater than threshold 3.09). GenCC has associacion of gene with spermatogenic failure 45.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0041172802).
• BP6: Variant 17-7831158-A-T is Benign according to our data. Variant chr17-7831158-A-T is described in ClinVar as [Benign]. Clinvar id is 402715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH2	NM_020877.5	c.12303A>T	p.Leu4101Phe	missense_variant	80/86	ENST00000572933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH2	ENST00000572933.6	c.12303A>T	p.Leu4101Phe	missense_variant	80/86	2	NM_020877.5	P1
DNAH2	ENST00000389173.6	c.12303A>T	p.Leu4101Phe	missense_variant	79/85	2		P1
DNAH2	ENST00000575105.1	c.3150A>T	p.Leu1050Phe	missense_variant	21/23	5

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3513 AN: 152102 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00727

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0514

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0245 AC: 6161 AN: 251444 Hom.: 118 AF XY: 0.0247 AC XY: 3363 AN XY: 135890

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0201

Gnomad ASJ exome AF: 0.0602

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00817

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0386

GnomAD4 exome AF: 0.0235 AC: 34421 AN: 1461848 Hom.: 556 Cov.: 32 AF XY: 0.0235 AC XY: 17121 AN XY: 727216

Gnomad4 AFR exome AF: 0.00541

Gnomad4 AMR exome AF: 0.0221

Gnomad4 ASJ exome AF: 0.0568

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00883

Gnomad4 FIN exome AF: 0.0496

Gnomad4 NFE exome AF: 0.0235

Gnomad4 OTH exome AF: 0.0293

GnomAD4 genome AF: 0.0231 AC: 3514 AN: 152220 Hom.: 62 Cov.: 32 AF XY: 0.0244 AC XY: 1815 AN XY: 74420

Gnomad4 AFR AF: 0.00727

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.0591

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.0514

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0285 Hom.: 30

Bravo AF: 0.0212

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0295 AC: 254

ExAC AF: 0.0232 AC: 2816

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0345

EpiControl AF: 0.0338

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNAH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 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). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	0.090
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	.;T;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	.;N;.
REVEL	Benign	0.083
Sift	Benign	0.050	.;D;.
Sift4G	Uncertain	0.055	.;.;T
Polyphen		0.41	B;B;.
Vest4		0.097
MutPred		0.34		Loss of ubiquitination at K4096 (P = 0.0992);Loss of ubiquitination at K4096 (P = 0.0992);.;
MPC		0.50
ClinPred		0.019	T
GERP RS		3.6
Varity_R		0.40
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs117465420; hg19: chr17-7734476; COSMIC: COSV66728303;