rs589623

Variant names:

• chr11-103211861-G-A
• rs589623
• NM_001080463.2:c.8612G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103211861-G-A
• chr11-103211861-G-C

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.8612G>A​(p.Arg2871Gln) variant causes a missense change. The variant allele was found at a frequency of 0.793 in 1,521,494 control chromosomes in the GnomAD database, including 480,082 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43913 hom., cov: 32)
  • Exomes 𝑓: 0.80 (436169 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.41
• Publications: 42 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 (MetaRNN=2.285225E-6).
• BP6: Variant 11-103211861-G-A is Benign according to our data. Variant chr11-103211861-G-A is described in ClinVar as Benign. ClinVar VariationId is 302073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.8612G>A	p.Arg2871Gln	missense	Exon 54 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.8612G>A	p.Arg2871Gln	missense	Exon 54 of 89	NP_001368.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.8612G>A	p.Arg2871Gln	missense	Exon 54 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.8612G>A	p.Arg2871Gln	missense	Exon 54 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+77442G>A		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114756 AN: 151872 Hom.: 43869 Cov.: 32

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.835

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.790

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.779

GnomAD2 exomes AF: 0.794 AC: 120667 AN: 152026 AF XY: 0.795

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.848

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.767

Gnomad FIN exome AF: 0.802

Gnomad NFE exome AF: 0.805

Gnomad OTH exome AF: 0.806

GnomAD4 exome AF: 0.797 AC: 1091217 AN: 1369504 Hom.: 436169 Cov.: 32 AF XY: 0.796 AC XY: 537112 AN XY: 674624

African (AFR) AF: 0.610 AC: 18859 AN: 30914

American (AMR) AF: 0.847 AC: 28416 AN: 33556

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 20709 AN: 24424

East Asian (EAS) AF: 0.731 AC: 25784 AN: 35270

South Asian (SAS) AF: 0.766 AC: 55036 AN: 71860

European-Finnish (FIN) AF: 0.802 AC: 38746 AN: 48326

Middle Eastern (MID) AF: 0.777 AC: 4272 AN: 5498

European-Non Finnish (NFE) AF: 0.804 AC: 854804 AN: 1063032

Other (OTH) AF: 0.787 AC: 44591 AN: 56624

GnomAD4 genome AF: 0.756 AC: 114855 AN: 151990 Hom.: 43913 Cov.: 32 AF XY: 0.756 AC XY: 56184 AN XY: 74278

African (AFR) AF: 0.621 AC: 25742 AN: 41436

American (AMR) AF: 0.835 AC: 12737 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 2938 AN: 3472

East Asian (EAS) AF: 0.777 AC: 4023 AN: 5176

South Asian (SAS) AF: 0.774 AC: 3732 AN: 4824

European-Finnish (FIN) AF: 0.790 AC: 8346 AN: 10570

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.804 AC: 54643 AN: 67936

Other (OTH) AF: 0.779 AC: 1646 AN: 2112

Alfa AF: 0.792 Hom.: 158007

Bravo AF: 0.754

TwinsUK AF: 0.803 AC: 2979

ALSPAC AF: 0.804 AC: 3099

ESP6500AA AF: 0.630 AC: 2258

ESP6500EA AF: 0.810 AC: 6501

ExAC AF: 0.741 AC: 70849

Asia WGS AF: 0.734 AC: 2544 AN: 3462

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Asphyxiating thoracic dystrophy 3 (3)
-	-	1	Jeune thoracic dystrophy (1)
-	-	1	not provided (1)
-	-	1	Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PhyloP100		4.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.099
Sift	Benign	0.23	T
Sift4G	Benign	0.30	T
Polyphen		0.72	P
Vest4		0.049
MPC		0.084
ClinPred		0.017	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.15
Mutation Taster		=93/7	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: rs589623; hg19: chr11-103082590; COSMIC: COSV62088525;