rs118191062

Variant names:

• chr11-103155417-T-C
• rs118191062
• NM_001080463.2:c.3660T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001377.3(DYNC2H1):​c.3660T>C​(p.Pro1220Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,612,412 control chromosomes in the GnomAD database, including 461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (30 hom., cov: 32)
  • Exomes 𝑓: 0.022 (431 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.124
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-103155417-T-C is Benign according to our data. Variant chr11-103155417-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 302028.
• BP7: Synonymous conserved (PhyloP=0.124 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0153 (2329/152062) while in subpopulation NFE AF = 0.024 (1626/67882). AF 95% confidence interval is 0.023. There are 30 homozygotes in GnomAd4. There are 1127 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.3660T>C	p.Pro1220Pro	synonymous	Exon 25 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.3660T>C	p.Pro1220Pro	synonymous	Exon 25 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.3660T>C	p.Pro1220Pro	synonymous	Exon 25 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.3660T>C	p.Pro1220Pro	synonymous	Exon 25 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+20998T>C		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2328 AN: 151948 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0164 AC: 4068 AN: 247908 AF XY: 0.0163

Gnomad AFR exome AF: 0.00370

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.0169

GnomAD4 exome AF: 0.0221 AC: 32273 AN: 1460350 Hom.: 431 Cov.: 34 AF XY: 0.0215 AC XY: 15621 AN XY: 726440

African (AFR) AF: 0.00314 AC: 105 AN: 33434

American (AMR) AF: 0.0109 AC: 487 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00610 AC: 159 AN: 26076

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39634

South Asian (SAS) AF: 0.00410 AC: 353 AN: 86088

European-Finnish (FIN) AF: 0.0248 AC: 1320 AN: 53302

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5754

European-Non Finnish (NFE) AF: 0.0258 AC: 28629 AN: 1111130

Other (OTH) AF: 0.0190 AC: 1147 AN: 60316

GnomAD4 genome AF: 0.0153 AC: 2329 AN: 152062 Hom.: 30 Cov.: 32 AF XY: 0.0152 AC XY: 1127 AN XY: 74358

African (AFR) AF: 0.00395 AC: 164 AN: 41526

American (AMR) AF: 0.0147 AC: 224 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3466

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5160

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4824

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0240 AC: 1626 AN: 67882

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.0205 Hom.: 32

Bravo AF: 0.0142

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0259

EpiControl AF: 0.0256

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.7
DANN	Benign	0.44
PhyloP100		0.12
Mutation Taster		=99/1	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: rs118191062; hg19: chr11-103026146; COSMIC: COSV62095203;