rs116872934

Variant names:

• chr11-103283029-G-C
• rs116872934
• NM_001080463.2:c.10855G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080463.2(DYNC2H1):​c.10855G>C​(p.Asp3619His) variant causes a missense change. The variant allele was found at a frequency of 0.00671 in 1,602,214 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (59 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.54
• Publications: 6 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

ENSG00000285878 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006396532).
• BP6: Variant 11-103283029-G-C is Benign according to our data. Variant chr11-103283029-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00628 (955/152112) while in subpopulation AMR AF = 0.0244 (373/15266). AF 95% confidence interval is 0.0224. There are 8 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.10855G>C	p.Asp3619His	missense	Exon 74 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.10834G>C	p.Asp3612His	missense	Exon 73 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.10855G>C	p.Asp3619His	missense	Exon 74 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.10834G>C	p.Asp3612His	missense	Exon 73 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+148610G>C		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 956 AN: 151994 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00650

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00789 AC: 1918 AN: 243014 AF XY: 0.00706

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.0295

Gnomad ASJ exome AF: 0.00533

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00159

Gnomad NFE exome AF: 0.00654

Gnomad OTH exome AF: 0.00716

GnomAD4 exome AF: 0.00675 AC: 9791 AN: 1450102 Hom.: 59 Cov.: 29 AF XY: 0.00660 AC XY: 4753 AN XY: 720410

African (AFR) AF: 0.00111 AC: 37 AN: 33216

American (AMR) AF: 0.0275 AC: 1199 AN: 43678

Ashkenazi Jewish (ASJ) AF: 0.00556 AC: 144 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39298

South Asian (SAS) AF: 0.00276 AC: 229 AN: 82940

European-Finnish (FIN) AF: 0.00113 AC: 60 AN: 53040

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5724

European-Non Finnish (NFE) AF: 0.00705 AC: 7801 AN: 1106396

Other (OTH) AF: 0.00519 AC: 311 AN: 59922

GnomAD4 genome AF: 0.00628 AC: 955 AN: 152112 Hom.: 8 Cov.: 32 AF XY: 0.00648 AC XY: 482 AN XY: 74376

African (AFR) AF: 0.00207 AC: 86 AN: 41502

American (AMR) AF: 0.0244 AC: 373 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00650 AC: 442 AN: 67948

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00612 Hom.: 1

Bravo AF: 0.00744

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00137 AC: 5

ESP6500EA AF: 0.00738 AC: 60

ExAC AF: 0.00688 AC: 831

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	2	not specified (2)
-	-	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	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.26
Sift	Benign	0.041	D
Sift4G	Benign	0.11	T
Polyphen		0.066	B
Vest4		0.57
MVP		0.41
MPC		0.075
ClinPred		0.015	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.38
Mutation Taster		=74/26	polymorphism

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: rs116872934; hg19: chr11-103153758; COSMIC: COSV100520203;