NM_001267550.2:c.104774A>C

Variant names:

• chr2-178531841-T-G
• rs201218828
• NM_001267550.2:c.104774A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.104774A>C​(p.Glu34925Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,860 control chromosomes in the GnomAD database, including 5 homozygotes. 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 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:15
• Conservation: PhyloP100: 8.01
• 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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015248656).
• BP6: Variant 2-178531841-T-G is Benign according to our data. Variant chr2-178531841-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178153.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00104 (158/152310) while in subpopulation NFE AF = 0.00198 (135/68020). AF 95% confidence interval is 0.00171. There are 1 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.104774A>C	p.Glu34925Ala	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.99851A>C	p.Glu33284Ala	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.97070A>C	p.Glu32357Ala	missense	Exon 307 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.104774A>C	p.Glu34925Ala	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.104618A>C	p.Glu34873Ala	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.104498A>C	p.Glu34833Ala	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00164 AC: 408 AN: 248550 AF XY: 0.00157

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00335

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00134 AC: 1961 AN: 1461550 Hom.: 4 Cov.: 40 AF XY: 0.00132 AC XY: 957 AN XY: 727034

African (AFR) AF: 0.000239 AC: 8 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00390 AC: 208 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00151 AC: 1684 AN: 1111790

Other (OTH) AF: 0.00101 AC: 61 AN: 60372

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74474

African (AFR) AF: 0.000168 AC: 7 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00198 AC: 135 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00149 Hom.: 1

Bravo AF: 0.000771

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.00228 AC: 276

EpiCase AF: 0.000709

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Cardiomyopathy (2)
-	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	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.92
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.55	N
PhyloP100		8.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.38
MVP		0.54
MPC		0.47
ClinPred		0.080	T
GERP RS		5.6
Mutation Taster		=85/15	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: rs201218828; hg19: chr2-179396568;