rs12994774

Variant names:

• chr2-178663311-A-C
• rs12994774
• NM_001267550.2:c.36655T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178663311-A-C
• chr2-178663311-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.36655T>G​(p.Leu12219Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.18 (2431 hom., cov: 23)
  • Exomes 𝑓: 0.11 (34361 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -4.21
• Publications: 11 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017544031).
• BP6: Variant 2-178663311-A-C is Benign according to our data. Variant chr2-178663311-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220982.

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.36655T>G	p.Leu12219Val	missense	Exon 173 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34265-256T>G		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31484-256T>G		intron	N/A	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.36655T>G	p.Leu12219Val	missense	Exon 173 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36655T>G	p.Leu12219Val	missense	Exon 173 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36379T>G	p.Leu12127Val	missense	Exon 171 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.177 AC: 20356 AN: 115166 Hom.: 2428 Cov.: 23

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.208

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.0997 AC: 21960 AN: 220158 AF XY: 0.0944

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.0592

Gnomad EAS exome AF: 0.333

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0503

Gnomad OTH exome AF: 0.118

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.105 AC: 137173 AN: 1302676 Hom.: 34361 Cov.: 34 AF XY: 0.111 AC XY: 71844 AN XY: 647128

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.177 AC: 5119 AN: 28992

American (AMR) AF: 0.191 AC: 7039 AN: 36772

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3679 AN: 23656

East Asian (EAS) AF: 0.494 AC: 16952 AN: 34308

South Asian (SAS) AF: 0.289 AC: 19912 AN: 68906

European-Finnish (FIN) AF: 0.127 AC: 6257 AN: 49314

Middle Eastern (MID) AF: 0.163 AC: 591 AN: 3636

European-Non Finnish (NFE) AF: 0.0697 AC: 69884 AN: 1003242

Other (OTH) AF: 0.144 AC: 7740 AN: 53850

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.177 AC: 20375 AN: 115242 Hom.: 2431 Cov.: 23 AF XY: 0.176 AC XY: 9706 AN XY: 55072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.210 AC: 6215 AN: 29608

American (AMR) AF: 0.223 AC: 2363 AN: 10616

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 501 AN: 2724

East Asian (EAS) AF: 0.448 AC: 1415 AN: 3162

South Asian (SAS) AF: 0.308 AC: 910 AN: 2958

European-Finnish (FIN) AF: 0.141 AC: 1162 AN: 8248

Middle Eastern (MID) AF: 0.212 AC: 51 AN: 240

European-Non Finnish (NFE) AF: 0.130 AC: 7233 AN: 55498

Other (OTH) AF: 0.175 AC: 285 AN: 1624

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.186 Hom.: 814

ExAC AF: 0.0689 AC: 8020

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.012
DANN	Benign	0.63
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.068	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
PhyloP100		-4.2
Vest4		0.026
MPC		0.084
ClinPred		0.00046	T
GERP RS		-4.3
Mutation Taster		=94/6	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: rs12994774; hg19: chr2-179528038; COSMIC: COSV59895468; COSMIC: COSV59895468;