rs200840285

Variant names:

• chr2-178663650-T-A
• rs200840285
• NM_001267550.2:c.36509A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178663650-T-A
• chr2-178663650-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.36509A>T​(p.Glu12170Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,613,690 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E12170K) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.59
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069047213).
• BP6: Variant 2-178663650-T-A is Benign according to our data. Variant chr2-178663650-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 192173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00214 (326/152230) while in subpopulation NFE AF = 0.00373 (254/68008). AF 95% confidence interval is 0.00336. There are 1 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

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.36509A>T	p.Glu12170Val	missense	Exon 171 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34265-595A>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31484-595A>T		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.36509A>T	p.Glu12170Val	missense	Exon 171 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36509A>T	p.Glu12170Val	missense	Exon 171 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36233A>T	p.Glu12078Val	missense	Exon 169 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 326 AN: 152116 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00373

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00228 AC: 563 AN: 247448 AF XY: 0.00233

Gnomad AFR exome AF: 0.000202

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000600

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00608

Gnomad NFE exome AF: 0.00347

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00292 AC: 4264 AN: 1461460 Hom.: 9 Cov.: 34 AF XY: 0.00294 AC XY: 2136 AN XY: 727014

African (AFR) AF: 0.000179 AC: 6 AN: 33462

American (AMR) AF: 0.000627 AC: 28 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86244

European-Finnish (FIN) AF: 0.00680 AC: 363 AN: 53402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00335 AC: 3726 AN: 1111740

Other (OTH) AF: 0.00192 AC: 116 AN: 60342

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152230 Hom.: 1 Cov.: 30 AF XY: 0.00212 AC XY: 158 AN XY: 74430

African (AFR) AF: 0.000385 AC: 16 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

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

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00373 AC: 254 AN: 68008

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00286 Hom.: 2

Bravo AF: 0.00164

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00377 AC: 15

ExAC AF: 0.00229 AC: 276

EpiCase AF: 0.00267

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Uncertain	0.99
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.82	T
PhyloP100		1.6
Vest4		0.25
MVP		0.64
ClinPred		0.023	T
GERP RS		3.8
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200840285; hg19: chr2-179528377;