rs61737514

Variant names:

• chr11-103323958-G-A
• rs61737514
• NM_001080463.2:c.12028G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103323958-G-A
• chr11-103323958-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001377.3(DYNC2H1):​c.12007G>A​(p.Ala4003Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,611,986 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4003G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (10 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 9.17
• Publications: 4 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), Ambry Genetics, Orphanet, G2P, ClinGen
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008333504).
• BP6: Variant 11-103323958-G-A is Benign according to our data. Variant chr11-103323958-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215482.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00559 (849/151990) while in subpopulation AFR AF = 0.019 (788/41426). AF 95% confidence interval is 0.0179. There are 6 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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_001377.3. 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.12028G>A	p.Ala4010Thr	missense	Exon 83 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.12007G>A	p.Ala4003Thr	missense	Exon 82 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.12028G>A	p.Ala4010Thr	missense	Exon 83 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.12007G>A	p.Ala4003Thr	missense	Exon 82 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2206-111985G>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 846 AN: 151872 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00528

GnomAD2 exomes AF: 0.00149 AC: 371 AN: 248632 AF XY: 0.00110

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000623 AC: 909 AN: 1459996 Hom.: 10 Cov.: 30 AF XY: 0.000548 AC XY: 398 AN XY: 726226

African (AFR) AF: 0.0189 AC: 631 AN: 33438

American (AMR) AF: 0.000873 AC: 39 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85976

European-Finnish (FIN) AF: 0.0000939 AC: 5 AN: 53246

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1110926

Other (OTH) AF: 0.00134 AC: 81 AN: 60296

GnomAD4 genome AF: 0.00559 AC: 849 AN: 151990 Hom.: 6 Cov.: 32 AF XY: 0.00557 AC XY: 414 AN XY: 74290

African (AFR) AF: 0.0190 AC: 788 AN: 41426

American (AMR) AF: 0.00170 AC: 26 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10544

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67998

Other (OTH) AF: 0.00522 AC: 11 AN: 2106

Alfa AF: 0.00246 Hom.: 14

Bravo AF: 0.00670

ESP6500AA AF: 0.0195 AC: 73

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00194 AC: 234

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.22
Sift	Benign	0.058	T
Sift4G	Benign	0.076	T
Polyphen		0.067	B
Vest4		0.54
MVP		0.58
MPC		0.066
ClinPred		0.039	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.36
Mutation Taster		=82/18	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: rs61737514; hg19: chr11-103194686;