rs118057786

Variant names:

• chr17-7759801-C-T
• rs118057786
• NM_020877.5:c.2648C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020877.5(DNAH2):​c.2648C>T​(p.Ser883Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0123 in 1,614,182 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (12 hom., cov: 32)
  • Exomes 𝑓: 0.013 (164 hom.)
• Consequence: DNAH2 NM_020877.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.85
• Publications: 11 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=0.017301321).
• BP6: Variant 17-7759801-C-T is Benign according to our data. Variant chr17-7759801-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00875 (1333/152340) while in subpopulation NFE AF = 0.0148 (1004/68020). AF 95% confidence interval is 0.014. There are 12 homozygotes in GnomAd4. There are 633 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.2648C>T	p.Ser883Leu	missense	Exon 17 of 86	NP_065928.2	Q9P225-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH2	ENST00000572933.6	TSL:2 MANE Select	c.2648C>T	p.Ser883Leu	missense	Exon 17 of 86	ENSP00000458355.1	Q9P225-1
	DNAH2	ENST00000389173.6	TSL:2	c.2648C>T	p.Ser883Leu	missense	Exon 16 of 85	ENSP00000373825.2	Q9P225-1

Frequencies

GnomAD3 genomes AF: 0.00876 AC: 1334 AN: 152222 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00821 AC: 2063 AN: 251396 AF XY: 0.00843

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00925

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.00897

GnomAD4 exome AF: 0.0126 AC: 18484 AN: 1461842 Hom.: 164 Cov.: 32 AF XY: 0.0125 AC XY: 9120 AN XY: 727220

African (AFR) AF: 0.00173 AC: 58 AN: 33480

American (AMR) AF: 0.00432 AC: 193 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00450 AC: 388 AN: 86256

European-Finnish (FIN) AF: 0.0104 AC: 558 AN: 53412

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5766

European-Non Finnish (NFE) AF: 0.0149 AC: 16564 AN: 1111976

Other (OTH) AF: 0.0113 AC: 681 AN: 60394

GnomAD4 genome AF: 0.00875 AC: 1333 AN: 152340 Hom.: 12 Cov.: 32 AF XY: 0.00850 AC XY: 633 AN XY: 74490

African (AFR) AF: 0.00224 AC: 93 AN: 41582

American (AMR) AF: 0.00673 AC: 103 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00838 AC: 89 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1004 AN: 68020

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.0120 Hom.: 28

Bravo AF: 0.00855

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.00843 AC: 1023

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0129

EpiControl AF: 0.0120

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	DNAH2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.15
Sift	Benign	0.15	T
Polyphen		0.67	P
Vest4		0.79
MVP		0.42
MPC		0.64
ClinPred		0.014	T
GERP RS		5.7
Varity_R		0.25
gMVP		0.47
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs118057786; hg19: chr17-7663119; COSMIC: COSV66716566; COSMIC: COSV66716566;