rs370627443

Variant names:

• chr11-103209902-A-C
• rs370627443
• NM_001080463.2:c.8481A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-103209902-A-C
• chr11-103209902-A-G
• chr11-103209902-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001377.3(DYNC2H1):​c.8481A>C​(p.Thr2827Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,495,460 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2827T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.16
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-103209902-A-C is Benign according to our data. Variant chr11-103209902-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284909.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.8481A>C	p.Thr2827Thr	synonymous	Exon 53 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.8481A>C	p.Thr2827Thr	synonymous	Exon 53 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.8481A>C	p.Thr2827Thr	synonymous	Exon 53 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.8481A>C	p.Thr2827Thr	synonymous	Exon 53 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+75483A>C		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 151992 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000741 AC: 92 AN: 124198 AF XY: 0.000636

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.000286

GnomAD4 exome AF: 0.00242 AC: 3247 AN: 1343350 Hom.: 8 Cov.: 27 AF XY: 0.00235 AC XY: 1554 AN XY: 661668

African (AFR) AF: 0.000173 AC: 5 AN: 28902

American (AMR) AF: 0.000105 AC: 3 AN: 28578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23892

East Asian (EAS) AF: 0.00 AC: 0 AN: 33450

South Asian (SAS) AF: 0.00 AC: 0 AN: 71254

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 0.00291 AC: 3053 AN: 1050706

Other (OTH) AF: 0.00333 AC: 185 AN: 55544

GnomAD4 genome AF: 0.00126 AC: 191 AN: 152110 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74364

African (AFR) AF: 0.000361 AC: 15 AN: 41580

American (AMR) AF: 0.000197 AC: 3 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 67872

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00133 Hom.: 1

Bravo AF: 0.00135

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	Asphyxiating thoracic dystrophy 3 (2)
-	-	1	Jeune thoracic dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.54
PhyloP100		1.2
Mutation Taster		=100/0	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: rs370627443; hg19: chr11-103080631;