chr11-103135828-G-A

Variant names:

• chr11-103135828-G-A
• rs77738279
• NM_001080463.2:c.2454G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001377.3(DYNC2H1):​c.2454G>A​(p.Glu818Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,612,950 control chromosomes in the GnomAD database, including 1,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (107 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1671 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.130
• Publications: 8 publications found

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, ClinGen
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR 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=-0.75).
• BP6: Variant 11-103135828-G-A is Benign according to our data. Variant chr11-103135828-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377.3. 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
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.2454G>A	p.Glu818Glu	synonymous	Exon 17 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.2454G>A	p.Glu818Glu	synonymous	Exon 17 of 89	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.2454G>A	p.Glu818Glu	synonymous	Exon 17 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.2454G>A	p.Glu818Glu	synonymous	Exon 17 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+1409G>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5087 AN: 152094 Hom.: 107 Cov.: 32

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.0644

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0445

Gnomad OTH AF: 0.0322

GnomAD2 exomes AF: 0.0412 AC: 10208 AN: 247832 AF XY: 0.0442

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.0336

Gnomad EAS exome AF: 0.0614

Gnomad FIN exome AF: 0.0367

Gnomad NFE exome AF: 0.0430

Gnomad OTH exome AF: 0.0419

GnomAD4 exome AF: 0.0453 AC: 66183 AN: 1460738 Hom.: 1671 Cov.: 31 AF XY: 0.0465 AC XY: 33772 AN XY: 726554

African (AFR) AF: 0.00619 AC: 207 AN: 33462

American (AMR) AF: 0.0208 AC: 925 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 881 AN: 26116

East Asian (EAS) AF: 0.0773 AC: 3063 AN: 39644

South Asian (SAS) AF: 0.0663 AC: 5712 AN: 86110

European-Finnish (FIN) AF: 0.0366 AC: 1951 AN: 53310

Middle Eastern (MID) AF: 0.0342 AC: 197 AN: 5762

European-Non Finnish (NFE) AF: 0.0456 AC: 50665 AN: 1111450

Other (OTH) AF: 0.0428 AC: 2582 AN: 60324

GnomAD4 genome AF: 0.0334 AC: 5087 AN: 152212 Hom.: 107 Cov.: 32 AF XY: 0.0335 AC XY: 2494 AN XY: 74422

African (AFR) AF: 0.00773 AC: 321 AN: 41550

American (AMR) AF: 0.0285 AC: 436 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3472

East Asian (EAS) AF: 0.0645 AC: 334 AN: 5176

South Asian (SAS) AF: 0.0695 AC: 334 AN: 4808

European-Finnish (FIN) AF: 0.0359 AC: 381 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0445 AC: 3025 AN: 68016

Other (OTH) AF: 0.0318 AC: 67 AN: 2104

Alfa AF: 0.0383 Hom.: 87

Bravo AF: 0.0308

Asia WGS AF: 0.0600 AC: 208 AN: 3476

EpiCase AF: 0.0461

EpiControl AF: 0.0485

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Jeune thoracic dystrophy (2)
-	-	2	not specified (2)
-	-	1	Asphyxiating thoracic dystrophy 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.3
DANN	Benign	0.49
PhyloP100		-0.13
Mutation Taster		=100/0	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: rs77738279; hg19: chr11-103006557; COSMIC: COSV62089578;