NM_001267550.2:c.95297C>T

Variant names:

• chr2-178545939-G-A
• rs191484894
• NM_001267550.2:c.95297C>T

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.95297C>T​(p.Ser31766Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,864 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S31766S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (47 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:23
• Conservation: PhyloP100: 8.05
• Publications: 12 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=0.011009574).
• BP6: Variant 2-178545939-G-A is Benign according to our data. Variant chr2-178545939-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47555.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00179 (273/152284) while in subpopulation SAS AF = 0.0238 (115/4824). AF 95% confidence interval is 0.0203. There are 5 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.95297C>T	p.Ser31766Phe	missense	Exon 343 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.90374C>T	p.Ser30125Phe	missense	Exon 293 of 313	NP_001243779.1
	TTN	NM_133378.4		c.87593C>T	p.Ser29198Phe	missense	Exon 292 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.95297C>T	p.Ser31766Phe	missense	Exon 343 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.95141C>T	p.Ser31714Phe	missense	Exon 341 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.95021C>T	p.Ser31674Phe	missense	Exon 341 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152166 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00369 AC: 918 AN: 248702 AF XY: 0.00471

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.000896

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00348

GnomAD4 exome AF: 0.00221 AC: 3230 AN: 1461580 Hom.: 47 Cov.: 32 AF XY: 0.00282 AC XY: 2053 AN XY: 727080

African (AFR) AF: 0.000418 AC: 14 AN: 33468

American (AMR) AF: 0.000693 AC: 31 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26130

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39690

South Asian (SAS) AF: 0.0210 AC: 1814 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53402

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00102 AC: 1134 AN: 1111782

Other (OTH) AF: 0.00297 AC: 179 AN: 60366

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152284 Hom.: 5 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74442

African (AFR) AF: 0.000241 AC: 10 AN: 41570

American (AMR) AF: 0.00183 AC: 28 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000972 Hom.: 0

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000501 AC: 2

ESP6500EA AF: 0.00192 AC: 16

ExAC AF: 0.00425 AC: 514

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	6	not provided (7)
-	-	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	Cardiomyopathy (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 dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.97
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.72
MPC		0.48
ClinPred		0.072	T
GERP RS		5.8
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs191484894; hg19: chr2-179410666;