NM_020877.5:c.12184A>C

Variant names:

• chr17-7830796-A-C
• rs79350244
• NM_020877.5:c.12184A>C

Variant summary

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

The NM_020877.5(DNAH2):​c.12184A>C​(p.Ile4062Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0236 in 1,614,040 control chromosomes in the GnomAD database, including 621 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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 (559 hom.)
• Consequence: DNAH2 NM_020877.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.60
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043467283).
• BP6: Variant 17-7830796-A-C is Benign according to our data. Variant chr17-7830796-A-C is described in ClinVar as Benign. ClinVar VariationId is 402714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH2	NM_020877.5	c.12184A>C	p.Ile4062Leu	missense_variant	Exon 79 of 86	ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6	c.12184A>C	p.Ile4062Leu	missense_variant	Exon 79 of 86	2	NM_020877.5	ENSP00000458355.1
DNAH2	ENST00000389173.6	c.12184A>C	p.Ile4062Leu	missense_variant	Exon 78 of 85	2		ENSP00000373825.2
DNAH2	ENST00000575105.1	c.3031A>C	p.Ile1011Leu	missense_variant	Exon 20 of 23	5		ENSP00000461726.1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3517 AN: 152152 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00727

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.0514

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0439

GnomAD2 exomes AF: 0.0246 AC: 6170 AN: 251170 AF XY: 0.0248

Gnomad AFR exome AF: 0.00635

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0603

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0236 AC: 34511 AN: 1461770 Hom.: 559 Cov.: 33 AF XY: 0.0236 AC XY: 17169 AN XY: 727168

African (AFR) AF: 0.00541 AC: 181 AN: 33480

American (AMR) AF: 0.0221 AC: 990 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 1485 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.00890 AC: 768 AN: 86258

European-Finnish (FIN) AF: 0.0496 AC: 2646 AN: 53300

Middle Eastern (MID) AF: 0.0855 AC: 493 AN: 5768

European-Non Finnish (NFE) AF: 0.0235 AC: 26169 AN: 1112010

Other (OTH) AF: 0.0293 AC: 1772 AN: 60394

GnomAD4 genome AF: 0.0231 AC: 3518 AN: 152270 Hom.: 62 Cov.: 32 AF XY: 0.0244 AC XY: 1819 AN XY: 74466

African (AFR) AF: 0.00727 AC: 302 AN: 41552

American (AMR) AF: 0.0347 AC: 531 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0590 AC: 205 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4828

European-Finnish (FIN) AF: 0.0514 AC: 546 AN: 10616

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0255 AC: 1736 AN: 68002

Other (OTH) AF: 0.0435 AC: 92 AN: 2116

Alfa AF: 0.0258 Hom.: 234

Bravo AF: 0.0213

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0298 AC: 256

ExAC AF: 0.0233 AC: 2824

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0345

EpiControl AF: 0.0340

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNAH2-related disorder Benign:1

May 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.036	T;T;.
Eigen	Benign	-0.014
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	.;T;D
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.23	N;N;.
PhyloP100		6.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	.;N;.
REVEL	Benign	0.16
Sift	Benign	0.28	.;T;.
Sift4G	Benign	0.21	.;.;T
Polyphen		0.52	P;P;.
Vest4		0.29
MPC		0.80
ClinPred		0.011	T
GERP RS		5.8
Varity_R		0.44
gMVP		0.62
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs79350244; hg19: chr17-7734114; COSMIC: COSV66728296;