rs17512054

Variant names:

• chr14-101986736-A-G
• rs17512054
• NM_001376.5:c.2511A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001376.5(DYNC1H1):​c.2511A>G​(p.Ala837Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,230 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (149 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.378
• Publications: 7 publications found

Genes affected

DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]

DYNC1H1 Gene-Disease associations (from GenCC):

• autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• intellectual disability, autosomal dominant 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• neuronopathy, distal hereditary motor

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2O

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 14-101986736-A-G is Benign according to our data. Variant chr14-101986736-A-G is described in ClinVar as Benign. ClinVar VariationId is 128924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.378 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00832 (1267/152340) while in subpopulation SAS AF = 0.0275 (133/4832). AF 95% confidence interval is 0.0237. There are 7 homozygotes in GnomAd4. There are 580 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1267 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376.5. 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
	DYNC1H1	NM_001376.5	MANE Select	c.2511A>G	p.Ala837Ala	synonymous	Exon 8 of 78	NP_001367.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.2511A>G	p.Ala837Ala	synonymous	Exon 8 of 78	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.2511A>G	p.Ala837Ala	synonymous	Exon 8 of 77	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.2511A>G	p.Ala837Ala	synonymous	Exon 8 of 78	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1267 AN: 152222 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0116 AC: 2890 AN: 249608 AF XY: 0.0130

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.0114 AC: 16719 AN: 1461890 Hom.: 149 Cov.: 32 AF XY: 0.0121 AC XY: 8835 AN XY: 727246

African (AFR) AF: 0.00152 AC: 51 AN: 33480

American (AMR) AF: 0.00932 AC: 417 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 321 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0288 AC: 2486 AN: 86256

European-Finnish (FIN) AF: 0.00575 AC: 307 AN: 53418

Middle Eastern (MID) AF: 0.0133 AC: 77 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12410 AN: 1112012

Other (OTH) AF: 0.0106 AC: 643 AN: 60396

GnomAD4 genome AF: 0.00832 AC: 1267 AN: 152340 Hom.: 7 Cov.: 32 AF XY: 0.00779 AC XY: 580 AN XY: 74496

African (AFR) AF: 0.00219 AC: 91 AN: 41578

American (AMR) AF: 0.00909 AC: 139 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0275 AC: 133 AN: 4832

European-Finnish (FIN) AF: 0.00414 AC: 44 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0115 AC: 785 AN: 68034

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.0105 Hom.: 13

Bravo AF: 0.00794

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0124

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Charcot-Marie-Tooth disease axonal type 2O (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.1
DANN	Benign	0.61
PhyloP100		-0.38
Mutation Taster		=97/3	polymorphism (auto)

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: rs17512054; hg19: chr14-102453073; COSMIC: COSV64137011;