rs368973334

Variant names:

• chr2-178696001-G-A
• rs368973334
• NM_001267550.2:c.31071C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178696001-G-A
• chr2-178696001-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001267550.2(TTN):​c.31071C>T​(p.His10357His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000634 in 1,545,176 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000073 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -1.17
• Publications: 2 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-178696001-G-A is Benign according to our data. Variant chr2-178696001-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166119.
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.31071C>T	p.His10357His	synonymous	Exon 114 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.30120C>T	p.His10040His	synonymous	Exon 112 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.27339C>T	p.His9113His	synonymous	Exon 111 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.31071C>T	p.His10357His	synonymous	Exon 114 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.31071C>T	p.His10357His	synonymous	Exon 114 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.30795C>T	p.His10265His	synonymous	Exon 112 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000726 AC: 11 AN: 151442 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000913 AC: 14 AN: 153288 AF XY: 0.0000740

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.000232

GnomAD4 exome AF: 0.0000624 AC: 87 AN: 1393734 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 34 AN XY: 687106

African (AFR) AF: 0.00 AC: 0 AN: 31304

American (AMR) AF: 0.000227 AC: 8 AN: 35310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24970

East Asian (EAS) AF: 0.00 AC: 0 AN: 35564

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.0000687 AC: 74 AN: 1076604

Other (OTH) AF: 0.0000693 AC: 4 AN: 57736

GnomAD4 genome AF: 0.0000726 AC: 11 AN: 151442 Hom.: 0 Cov.: 32 AF XY: 0.0000677 AC XY: 5 AN XY: 73890

African (AFR) AF: 0.0000485 AC: 2 AN: 41206

American (AMR) AF: 0.0000659 AC: 1 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67794

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.032
DANN	Benign	0.77
PhyloP100		-1.2
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368973334; hg19: chr2-179560728;