11-103152201-T-C

Variant names:

• chr11-103152201-T-C
• rs202082545
• NM_001080463.2:c.3012T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001080463.2(DYNC2H1):​c.3012T>C​(p.Gly1004Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,606,482 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1004G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.356
• Publications: 1 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), G2P, Orphanet, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-103152201-T-C is Benign according to our data. Variant chr11-103152201-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 302024.
• BP7: Synonymous conserved (PhyloP=0.356 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0033 (500/151422) while in subpopulation AFR AF = 0.011 (455/41326). AF 95% confidence interval is 0.0102. There are 6 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. 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
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.3012T>C	p.Gly1004Gly	synonymous	Exon 21 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.3012T>C	p.Gly1004Gly	synonymous	Exon 21 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.3012T>C	p.Gly1004Gly	synonymous	Exon 21 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.3012T>C	p.Gly1004Gly	synonymous	Exon 21 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+17782T>C		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 499 AN: 151314 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00113 AC: 273 AN: 241642 AF XY: 0.000922

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.000510

GnomAD4 exome AF: 0.000518 AC: 754 AN: 1455060 Hom.: 8 Cov.: 33 AF XY: 0.000547 AC XY: 396 AN XY: 723350

African (AFR) AF: 0.0117 AC: 389 AN: 33234

American (AMR) AF: 0.00100 AC: 44 AN: 43860

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39046

South Asian (SAS) AF: 0.00152 AC: 129 AN: 84656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52814

Middle Eastern (MID) AF: 0.00300 AC: 17 AN: 5666

European-Non Finnish (NFE) AF: 0.0000793 AC: 88 AN: 1109666

Other (OTH) AF: 0.00141 AC: 85 AN: 60078

GnomAD4 genome AF: 0.00330 AC: 500 AN: 151422 Hom.: 6 Cov.: 31 AF XY: 0.00318 AC XY: 235 AN XY: 73946

African (AFR) AF: 0.0110 AC: 455 AN: 41326

American (AMR) AF: 0.00125 AC: 19 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10404

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67836

Other (OTH) AF: 0.00285 AC: 6 AN: 2104

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00377

Asia WGS AF: 0.00116 AC: 4 AN: 3462

EpiCase AF: 0.000166

EpiControl AF: 0.0000601

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Jeune thoracic dystrophy (2)
-	-	2	not specified (2)
-	-	1	Asphyxiating thoracic dystrophy 3 (1)
-	1	-	Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.4
DANN	Benign	0.73
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202082545; hg19: chr11-103022930;