rs112718117

Variant names:

• chr11-103109776-T-C
• rs112718117
• NM_001080463.2:c.195+7T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-103109776-T-C
• chr11-103109776-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001080463.2(DYNC2H1):​c.195+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00984 in 1,609,006 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (137 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003429
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -1.48
• 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), 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-103109776-T-C is Benign according to our data. Variant chr11-103109776-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 301996.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

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.195+7T>C		splice_region intron	N/A	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.195+7T>C		splice_region intron	N/A	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.195+7T>C		splice_region intron	N/A	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.195+7T>C		splice_region intron	N/A	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.195+7T>C		splice_region intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1811 AN: 151712 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.0557

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00285

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.0106 AC: 2609 AN: 245900 AF XY: 0.0104

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0484

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00357

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.00963 AC: 14033 AN: 1457176 Hom.: 137 Cov.: 31 AF XY: 0.00978 AC XY: 7085 AN XY: 724270

African (AFR) AF: 0.0137 AC: 457 AN: 33438

American (AMR) AF: 0.0107 AC: 476 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.0523 AC: 1353 AN: 25894

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.00375 AC: 322 AN: 85786

European-Finnish (FIN) AF: 0.00455 AC: 242 AN: 53230

Middle Eastern (MID) AF: 0.0585 AC: 316 AN: 5404

European-Non Finnish (NFE) AF: 0.00895 AC: 9924 AN: 1109036

Other (OTH) AF: 0.0157 AC: 942 AN: 60160

GnomAD4 genome AF: 0.0119 AC: 1805 AN: 151830 Hom.: 23 Cov.: 32 AF XY: 0.0115 AC XY: 850 AN XY: 74178

African (AFR) AF: 0.0131 AC: 542 AN: 41378

American (AMR) AF: 0.0137 AC: 209 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.0557 AC: 193 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4812

European-Finnish (FIN) AF: 0.00285 AC: 30 AN: 10536

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 752 AN: 67964

Other (OTH) AF: 0.0180 AC: 38 AN: 2108

Alfa AF: 0.0123 Hom.: 9

Bravo AF: 0.0130

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.62
PhyloP100		-1.5
PromoterAI		-0.10	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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: rs112718117; hg19: chr11-102980505;