NM_001080463.2:c.2860G>A

Variant names:

• chr11-103148531-G-A
• rs61898615
• NM_001080463.2:c.2860G>A

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.2860G>A​(p.Glu954Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0148 in 1,565,512 control chromosomes in the GnomAD database, including 226 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E954E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 33)
  • Exomes 𝑓: 0.015 (208 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.92
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026997924).
• BP6: Variant 11-103148531-G-A is Benign according to our data. Variant chr11-103148531-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 188134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0122 (1860/152220) while in subpopulation SAS AF = 0.0233 (112/4814). AF 95% confidence interval is 0.0198. There are 18 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.2860G>A	p.Glu954Lys	missense	Exon 20 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.2860G>A	p.Glu954Lys	missense	Exon 20 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.2860G>A	p.Glu954Lys	missense	Exon 20 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.2860G>A	p.Glu954Lys	missense	Exon 20 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+14112G>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1857 AN: 152102 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0163 AC: 2931 AN: 179972 AF XY: 0.0162

Gnomad AFR exome AF: 0.00298

Gnomad AMR exome AF: 0.0306

Gnomad ASJ exome AF: 0.00422

Gnomad EAS exome AF: 0.000152

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0150 AC: 21240 AN: 1413292 Hom.: 208 Cov.: 30 AF XY: 0.0154 AC XY: 10736 AN XY: 698332

African (AFR) AF: 0.00235 AC: 76 AN: 32294

American (AMR) AF: 0.0284 AC: 1076 AN: 37844

Ashkenazi Jewish (ASJ) AF: 0.00369 AC: 94 AN: 25454

East Asian (EAS) AF: 0.0000802 AC: 3 AN: 37406

South Asian (SAS) AF: 0.0238 AC: 1913 AN: 80214

European-Finnish (FIN) AF: 0.0131 AC: 662 AN: 50424

Middle Eastern (MID) AF: 0.0169 AC: 96 AN: 5694

European-Non Finnish (NFE) AF: 0.0152 AC: 16526 AN: 1085380

Other (OTH) AF: 0.0136 AC: 794 AN: 58582

GnomAD4 genome AF: 0.0122 AC: 1860 AN: 152220 Hom.: 18 Cov.: 33 AF XY: 0.0122 AC XY: 907 AN XY: 74416

African (AFR) AF: 0.00289 AC: 120 AN: 41558

American (AMR) AF: 0.0145 AC: 221 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0233 AC: 112 AN: 4814

European-Finnish (FIN) AF: 0.0176 AC: 187 AN: 10608

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0169 AC: 1152 AN: 67998

Other (OTH) AF: 0.0133 AC: 28 AN: 2104

Alfa AF: 0.0155 Hom.: 77

Bravo AF: 0.0113

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00356 AC: 13

ESP6500EA AF: 0.0145 AC: 118

ExAC AF: 0.0112 AC: 1329

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	2	Jeune thoracic dystrophy (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.9
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.080
Sift	Benign	0.088	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.086
MPC		0.069
ClinPred		0.024	T
GERP RS		4.7
Varity_R		0.099
gMVP		0.27
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61898615; hg19: chr11-103019260;