rs12283022

Variant names:

• chr11-103109865-A-G
• rs12283022
• NM_001080463.2:c.195+96A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080463.2(DYNC2H1):​c.195+96A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,301,562 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (291 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (232 hom.)
• Consequence: DYNC2H1 NM_001080463.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.11
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-103109865-A-G is Benign according to our data. Variant chr11-103109865-A-G is described in ClinVar as Benign. ClinVar VariationId is 676692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.195+96A>G		intron_variant	Intron 1 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.195+96A>G		intron_variant	Intron 1 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.195+96A>G		intron_variant	Intron 1 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.195+96A>G		intron_variant	Intron 1 of 88	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5073 AN: 151872 Hom.: 291 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0245

GnomAD4 exome AF: 0.00348 AC: 4000 AN: 1149572 Hom.: 232 AF XY: 0.00301 AC XY: 1695 AN XY: 563546

African (AFR) AF: 0.125 AC: 3237 AN: 25920

American (AMR) AF: 0.00736 AC: 161 AN: 21878

Ashkenazi Jewish (ASJ) AF: 0.0000553 AC: 1 AN: 18090

East Asian (EAS) AF: 0.00 AC: 0 AN: 35216

South Asian (SAS) AF: 0.000153 AC: 9 AN: 58824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40184

Middle Eastern (MID) AF: 0.0105 AC: 35 AN: 3318

European-Non Finnish (NFE) AF: 0.000162 AC: 145 AN: 897190

Other (OTH) AF: 0.00842 AC: 412 AN: 48952

GnomAD4 genome AF: 0.0334 AC: 5074 AN: 151990 Hom.: 291 Cov.: 32 AF XY: 0.0317 AC XY: 2357 AN XY: 74286

African (AFR) AF: 0.116 AC: 4813 AN: 41422

American (AMR) AF: 0.0119 AC: 182 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000383 AC: 26 AN: 67970

Other (OTH) AF: 0.0242 AC: 51 AN: 2104

Alfa AF: 0.0384 Hom.: 43

Bravo AF: 0.0384

Asia WGS AF: 0.00606 AC: 22 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

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.63
DANN	Benign	0.19
PhyloP100		-2.1
PromoterAI		0.042	Neutral
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: rs12283022; hg19: chr11-102980594;