rs16866378

Variant names:

• chr2-178528384-A-G
• rs16866378
• NM_001267550.2:c.107267T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.107267T>C​(p.Val35756Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0326 in 1,613,920 control chromosomes in the GnomAD database, including 1,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V35756V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (464 hom., cov: 33)
  • Exomes 𝑓: 0.030 (1507 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 4.26
• Publications: 22 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001306057).
• BP6: Variant 2-178528384-A-G is Benign according to our data. Variant chr2-178528384-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

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.107267T>C	p.Val35756Ala	missense	Exon 361 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.102344T>C	p.Val34115Ala	missense	Exon 311 of 313	NP_001243779.1
	TTN	NM_133378.4		c.99563T>C	p.Val33188Ala	missense	Exon 310 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.107267T>C	p.Val35756Ala	missense	Exon 361 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.107111T>C	p.Val35704Ala	missense	Exon 359 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.106991T>C	p.Val35664Ala	missense	Exon 359 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8751 AN: 152178 Hom.: 464 Cov.: 33

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.0468

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0438 AC: 10910 AN: 248972 AF XY: 0.0430

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.0338

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.00353

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0411

GnomAD4 exome AF: 0.0300 AC: 43883 AN: 1461624 Hom.: 1507 Cov.: 32 AF XY: 0.0302 AC XY: 21941 AN XY: 727086

African (AFR) AF: 0.129 AC: 4313 AN: 33474

American (AMR) AF: 0.0364 AC: 1627 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 1111 AN: 26128

East Asian (EAS) AF: 0.179 AC: 7100 AN: 39692

South Asian (SAS) AF: 0.0491 AC: 4239 AN: 86254

European-Finnish (FIN) AF: 0.00333 AC: 178 AN: 53398

Middle Eastern (MID) AF: 0.0995 AC: 574 AN: 5768

European-Non Finnish (NFE) AF: 0.0201 AC: 22364 AN: 1111824

Other (OTH) AF: 0.0394 AC: 2377 AN: 60368

GnomAD4 genome AF: 0.0576 AC: 8768 AN: 152296 Hom.: 464 Cov.: 33 AF XY: 0.0574 AC XY: 4274 AN XY: 74490

African (AFR) AF: 0.127 AC: 5276 AN: 41544

American (AMR) AF: 0.0455 AC: 696 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.166 AC: 861 AN: 5186

South Asian (SAS) AF: 0.0472 AC: 228 AN: 4826

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10626

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1376 AN: 68022

Other (OTH) AF: 0.0629 AC: 133 AN: 2114

Alfa AF: 0.0358 Hom.: 885

Bravo AF: 0.0636

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.119 AC: 443

ESP6500EA AF: 0.0207 AC: 170

ExAC AF: 0.0446 AC: 5384

Asia WGS AF: 0.0990 AC: 343 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0291

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.64
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.050
MPC		0.10
ClinPred		0.011	T
GERP RS		1.2
Mutation Taster		=88/12	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: rs16866378; hg19: chr2-179393111; COSMIC: COSV107419465; COSMIC: COSV107419465;