rs199568537

Variant names:

• chr11-103219963-G-A
• rs199568537
• NM_001080463.2:c.8881G>A

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.8881G>A​(p.Ala2961Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,510,838 control chromosomes in the GnomAD database, including 14 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. A2961V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (13 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 8.53
• 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), 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=0.008848041).
• BP6: Variant 11-103219963-G-A is Benign according to our data. Variant chr11-103219963-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93530.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00312 (475/152262) while in subpopulation NFE AF = 0.00472 (321/68002). AF 95% confidence interval is 0.00429. There are 1 homozygotes in GnomAd4. There are 212 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.8881G>A	p.Ala2961Thr	missense	Exon 56 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.8881G>A	p.Ala2961Thr	missense	Exon 56 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.8881G>A	p.Ala2961Thr	missense	Exon 56 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.8881G>A	p.Ala2961Thr	missense	Exon 56 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+85544G>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152144 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00228 AC: 300 AN: 131426 AF XY: 0.00240

Gnomad AFR exome AF: 0.000880

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000388

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00394 AC: 5353 AN: 1358576 Hom.: 13 Cov.: 29 AF XY: 0.00383 AC XY: 2572 AN XY: 671818

African (AFR) AF: 0.000595 AC: 16 AN: 26904

American (AMR) AF: 0.00141 AC: 32 AN: 22674

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 77 AN: 23122

East Asian (EAS) AF: 0.00 AC: 0 AN: 32952

South Asian (SAS) AF: 0.000776 AC: 54 AN: 69616

European-Finnish (FIN) AF: 0.000591 AC: 30 AN: 50782

Middle Eastern (MID) AF: 0.00216 AC: 12 AN: 5566

European-Non Finnish (NFE) AF: 0.00462 AC: 4952 AN: 1070788

Other (OTH) AF: 0.00320 AC: 180 AN: 56172

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152262 Hom.: 1 Cov.: 33 AF XY: 0.00285 AC XY: 212 AN XY: 74456

African (AFR) AF: 0.00130 AC: 54 AN: 41564

American (AMR) AF: 0.00399 AC: 61 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00472 AC: 321 AN: 68002

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00315 Hom.: 14

Bravo AF: 0.00336

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000561 AC: 2

ESP6500EA AF: 0.00593 AC: 48

ExAC AF: 0.00178 AC: 212

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	1	DYNC2H1-related disorder (1)
-	-	1	Jeune thoracic dystrophy (1)
-	-	1	not specified (1)
-	1	-	Renal cyst (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.018	D
Sift4G	Benign	0.31	T
Polyphen		0.63	P
Vest4		0.34
MVP		0.77
MPC		0.15
ClinPred		0.020	T
GERP RS		5.8
Varity_R		0.41
gMVP		0.35
Mutation Taster		=27/73	disease causing

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: rs199568537; hg19: chr11-103090692;