NM_001206927.2:c.5185A>C

Variant names:

• chr6-38848787-A-C
• rs148767488
• NM_001206927.2:c.5185A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001206927.2(DNAH8):​c.5185A>C​(p.Lys1729Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.11
• Publications: 4 publications found

Genes affected

DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

DNAH8 Gene-Disease associations (from GenCC):

• spermatogenic failure 46

  Inheritance: AR Classification: STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• spermatogenic failure 5

  Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35040247).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. 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
	DNAH8	NM_001206927.2	MANE Select	c.5185A>C	p.Lys1729Gln	missense	Exon 37 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.4534A>C	p.Lys1512Gln	missense	Exon 36 of 92	NP_001362.2	Q96JB1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.5185A>C	p.Lys1729Gln	missense	Exon 37 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.4534A>C	p.Lys1512Gln	missense	Exon 35 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.5185A>C	p.Lys1729Gln	missense	Exon 36 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000323

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 250944 AF XY: 0.000184

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000296 AC: 433 AN: 1461142 Hom.: 0 Cov.: 30 AF XY: 0.000277 AC XY: 201 AN XY: 726880

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.000380 AC: 17 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.000361 AC: 401 AN: 1111502

Other (OTH) AF: 0.000215 AC: 13 AN: 60356

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74454

African (AFR) AF: 0.0000722 AC: 3 AN: 41556

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000342 Hom.: 1

Bravo AF: 0.000291

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.78
MPC		0.59
ClinPred		0.35	T
GERP RS		5.8
Varity_R		0.76
gMVP		0.33
Mutation Taster		=63/37	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: rs148767488; hg19: chr6-38816563;