6-38823020-G-C

Variant names:

• chr6-38823020-G-C
• rs201420305
• NM_001206927.2:c.3706G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001206927.2(DNAH8):​c.3706G>C​(p.Asp1236His) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,574,572 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1236N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.55
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1135613).

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.3706G>C	p.Asp1236His	missense	Exon 27 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.3055G>C	p.Asp1019His	missense	Exon 26 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.3706G>C	p.Asp1236His	missense	Exon 27 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.3055G>C	p.Asp1019His	missense	Exon 25 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.3706G>C	p.Asp1236His	missense	Exon 26 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000294 AC: 63 AN: 214582 AF XY: 0.000325

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000863

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000148

Gnomad NFE exome AF: 0.000542

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000266 AC: 378 AN: 1422446 Hom.: 0 Cov.: 30 AF XY: 0.000260 AC XY: 184 AN XY: 706546

African (AFR) AF: 0.0000320 AC: 1 AN: 31286

American (AMR) AF: 0.00 AC: 0 AN: 33428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39132

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.000114 AC: 6 AN: 52616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.000334 AC: 367 AN: 1098858

Other (OTH) AF: 0.0000684 AC: 4 AN: 58472

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74314

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000346 AC: 42

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.078
Sift	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.43
MVP		0.49
MPC		0.15
ClinPred		0.035	T
GERP RS		3.7
Varity_R		0.076
gMVP		0.55
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs201420305; hg19: chr6-38790796;