chr2-178728625-C-T

Variant names:

• chr2-178728625-C-T
• rs11888217
• NM_001267550.2:c.19301G>A

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.19301G>A​(p.Ser6434Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,613,134 control chromosomes in the GnomAD database, including 3,330 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (417 hom., cov: 33)
  • Exomes 𝑓: 0.042 (2913 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.52
• Publications: 15 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=0.0014732778).
• BP6: Variant 2-178728625-C-T is Benign according to our data. Variant chr2-178728625-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.19301G>A	p.Ser6434Asn	missense	Exon 66 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.18350G>A	p.Ser6117Asn	missense	Exon 64 of 313	NP_001243779.1
	TTN	NM_133378.4		c.15569G>A	p.Ser5190Asn	missense	Exon 63 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.19301G>A	p.Ser6434Asn	missense	Exon 66 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.19301G>A	p.Ser6434Asn	missense	Exon 66 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.19025G>A	p.Ser6342Asn	missense	Exon 64 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9055 AN: 152054 Hom.: 406 Cov.: 33

Gnomad AFR AF: 0.0821

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0458

GnomAD2 exomes AF: 0.0741 AC: 18372 AN: 247832 AF XY: 0.0728

Gnomad AFR exome AF: 0.0830

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.0264

Gnomad FIN exome AF: 0.0563

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0584

GnomAD4 exome AF: 0.0422 AC: 61711 AN: 1460962 Hom.: 2913 Cov.: 33 AF XY: 0.0448 AC XY: 32578 AN XY: 726736

African (AFR) AF: 0.0836 AC: 2797 AN: 33450

American (AMR) AF: 0.183 AC: 8164 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 932 AN: 26114

East Asian (EAS) AF: 0.0126 AC: 500 AN: 39600

South Asian (SAS) AF: 0.166 AC: 14345 AN: 86222

European-Finnish (FIN) AF: 0.0579 AC: 3090 AN: 53342

Middle Eastern (MID) AF: 0.0507 AC: 292 AN: 5764

European-Non Finnish (NFE) AF: 0.0258 AC: 28700 AN: 1111548

Other (OTH) AF: 0.0479 AC: 2891 AN: 60320

GnomAD4 genome AF: 0.0597 AC: 9086 AN: 152172 Hom.: 417 Cov.: 33 AF XY: 0.0644 AC XY: 4795 AN XY: 74400

African (AFR) AF: 0.0824 AC: 3424 AN: 41534

American (AMR) AF: 0.139 AC: 2129 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3470

East Asian (EAS) AF: 0.0244 AC: 126 AN: 5166

South Asian (SAS) AF: 0.167 AC: 804 AN: 4816

European-Finnish (FIN) AF: 0.0573 AC: 607 AN: 10602

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0256 AC: 1738 AN: 67988

Other (OTH) AF: 0.0454 AC: 96 AN: 2116

Alfa AF: 0.0332 Hom.: 457

Bravo AF: 0.0631

TwinsUK AF: 0.0240 AC: 89

ALSPAC AF: 0.0241 AC: 93

ESP6500AA AF: 0.0834 AC: 307

ESP6500EA AF: 0.0246 AC: 202

ExAC AF: 0.0693 AC: 8367

Asia WGS AF: 0.115 AC: 397 AN: 3478

EpiCase AF: 0.0247

EpiControl AF: 0.0251

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.89
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.79	T
PhyloP100		1.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Benign	0.38	T
Polyphen		0.55	P
Vest4		0.082
MPC		0.14
ClinPred		0.020	T
GERP RS		4.7
Mutation Taster		=86/14	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: rs11888217; hg19: chr2-179593352; COSMIC: COSV60092659; COSMIC: COSV60092659;