2-84525660-A-C

Variant names:

• chr2-84525660-A-C
• rs73945104
• NM_001370.2:c.321A>C

Variant summary

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

The NM_001370.2(DNAH6):​c.321A>C​(p.Pro107Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,550,696 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (16 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01

Genes affected

DNAH6 (HGNC:2951): (dynein axonemal heavy chain 6) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Mutations in this gene may cause primary ciliary dyskinesia (PCD) as well as heterotaxy. [provided by RefSeq, Jun 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-84525660-A-C is Benign according to our data. Variant chr2-84525660-A-C is described in ClinVar as [Benign]. Clinvar id is 783979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00953 (1451/152290) while in subpopulation AFR AF = 0.0336 (1398/41566). AF 95% confidence interval is 0.0322. There are 21 homozygotes in GnomAd4. There are 668 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.321A>C	p.Pro107Pro	synonymous_variant	Exon 3 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.321A>C	p.Pro107Pro	synonymous_variant	Exon 3 of 77	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000494025.1	n.229+7609A>C		intron_variant	Intron 1 of 8	1
DNAH6	ENST00000468661.1	n.376A>C		non_coding_transcript_exon_variant	Exon 3 of 4	4
DNAH6	ENST00000476689.5	n.458A>C		non_coding_transcript_exon_variant	Exon 3 of 11	2

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1447 AN: 152172 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00210 AC: 328 AN: 156046 AF XY: 0.00168

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.000965 AC: 1350 AN: 1398406 Hom.: 16 Cov.: 30 AF XY: 0.000812 AC XY: 560 AN XY: 689720

African (AFR) AF: 0.0360 AC: 1134 AN: 31534

American (AMR) AF: 0.00149 AC: 53 AN: 35636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25140

East Asian (EAS) AF: 0.00 AC: 0 AN: 35656

South Asian (SAS) AF: 0.000152 AC: 12 AN: 79172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49270

Middle Eastern (MID) AF: 0.000704 AC: 4 AN: 5682

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1078366

Other (OTH) AF: 0.00228 AC: 132 AN: 57950

GnomAD4 genome AF: 0.00953 AC: 1451 AN: 152290 Hom.: 21 Cov.: 32 AF XY: 0.00897 AC XY: 668 AN XY: 74474

African (AFR) AF: 0.0336 AC: 1398 AN: 41566

American (AMR) AF: 0.00216 AC: 33 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00758 Hom.: 11

Bravo AF: 0.0110

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.54
PhyloP100		1.0
Mutation Taster		=100/0	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

Publications

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Other links and lift over

dbSNP: rs73945104; hg19: chr2-84752784;