chr6-38723193-G-C

Variant names:

• chr6-38723193-G-C
• rs116164504
• NM_001206927.2:c.384G>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.384G>C​(p.Glu128Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,606,388 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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. E128K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.24
• Publications: 1 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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=0.078351825).

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.384G>C	p.Glu128Asp	missense	Exon 2 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.-183G>C		5_prime_UTR	Exon 2 of 92	NP_001362.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.384G>C	p.Glu128Asp	missense	Exon 2 of 93	ENSP00000333363.7
	DNAH8	ENST00000373278.8	TSL:1	c.384G>C	p.Glu128Asp	missense	Exon 2 of 5	ENSP00000362375.4
	DNAH8	ENST00000449981.6	TSL:5	c.384G>C	p.Glu128Asp	missense	Exon 1 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000299 AC: 71 AN: 237516 AF XY: 0.000338

Gnomad AFR exome AF: 0.000212

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000630

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000476 AC: 692 AN: 1454070 Hom.: 1 Cov.: 32 AF XY: 0.000475 AC XY: 343 AN XY: 722862

African (AFR) AF: 0.0000301 AC: 1 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 43568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 85126

European-Finnish (FIN) AF: 0.0000388 AC: 2 AN: 51530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.000609 AC: 676 AN: 1109352

Other (OTH) AF: 0.000216 AC: 13 AN: 60114

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74484

African (AFR) AF: 0.000192 AC: 8 AN: 41574

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000648 Hom.: 0

Bravo AF: 0.000306

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000571 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000267 AC: 31

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.83
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Uncertain	0.019	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.25		Loss of methylation at K127 (P = 0.1385)
MVP		0.75
ClinPred		0.13	T
GERP RS		4.2
PromoterAI		0.0022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.39
Mutation Taster		=279/21	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: rs116164504; hg19: chr6-38690969;