11-103454257-G-C

Variant names:

• chr11-103454257-G-C
• rs313877
• NM_001080463.2:c.12478-929G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080463.2(DYNC2H1):​c.12478-929G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 151,886 control chromosomes in the GnomAD database, including 7,145 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (7145 hom., cov: 32)
• Consequence: DYNC2H1 NM_001080463.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.216
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.12478-929G>C		intron_variant	Intron 86 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.12457-929G>C		intron_variant	Intron 85 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.12478-929G>C		intron_variant	Intron 86 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.12457-929G>C		intron_variant	Intron 85 of 88	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43212 AN: 151768 Hom.: 7128 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.250

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.285 AC: 43263 AN: 151886 Hom.: 7145 Cov.: 32 AF XY: 0.282 AC XY: 20954 AN XY: 74268

African (AFR) AF: 0.451 AC: 18700 AN: 41420

American (AMR) AF: 0.201 AC: 3065 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3462

East Asian (EAS) AF: 0.282 AC: 1461 AN: 5182

South Asian (SAS) AF: 0.267 AC: 1288 AN: 4816

European-Finnish (FIN) AF: 0.245 AC: 2590 AN: 10554

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14871 AN: 67888

Other (OTH) AF: 0.253 AC: 532 AN: 2106

Alfa AF: 0.261 Hom.: 722

Bravo AF: 0.288

Asia WGS AF: 0.294 AC: 1022 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.63
PhyloP100		-0.22
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: rs313877; hg19: chr11-103324985;