rs16866477

Variant names:

• chr2-178731454-G-C
• rs16866477
• NM_001267550.2:c.17312C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178731454-G-C
• chr2-178731454-G-A

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.17312C>G​(p.Thr5771Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,740 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (12 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 2.00
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047355294).
• BP6: Variant 2-178731454-G-C is Benign according to our data. Variant chr2-178731454-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 177967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00584 (889/152230) while in subpopulation AFR AF = 0.0205 (851/41542). AF 95% confidence interval is 0.0193. There are 6 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.17312C>G	p.Thr5771Ser	missense	Exon 59 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.16361C>G	p.Thr5454Ser	missense	Exon 57 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.13580C>G	p.Thr4527Ser	missense	Exon 56 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.17312C>G	p.Thr5771Ser	missense	Exon 59 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.17312C>G	p.Thr5771Ser	missense	Exon 59 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.17036C>G	p.Thr5679Ser	missense	Exon 57 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 885 AN: 152112 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00143 AC: 355 AN: 248692 AF XY: 0.00106

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000634 AC: 927 AN: 1461510 Hom.: 12 Cov.: 36 AF XY: 0.000554 AC XY: 403 AN XY: 727032

African (AFR) AF: 0.0231 AC: 772 AN: 33460

American (AMR) AF: 0.000940 AC: 42 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111766

Other (OTH) AF: 0.00142 AC: 86 AN: 60360

GnomAD4 genome AF: 0.00584 AC: 889 AN: 152230 Hom.: 6 Cov.: 33 AF XY: 0.00540 AC XY: 402 AN XY: 74426

African (AFR) AF: 0.0205 AC: 851 AN: 41542

American (AMR) AF: 0.000982 AC: 15 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.000390 Hom.: 0

Bravo AF: 0.00674

ESP6500AA AF: 0.0169 AC: 65

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.00191 AC: 231

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	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	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.77
Eigen	Benign	-0.093
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.079
Sift	Benign	0.90	T
Polyphen		0.061	B
Vest4		0.23
MutPred		0.29		Gain of disorder (P = 0.0749)
MVP		0.13
MPC		0.083
ClinPred		0.0088	T
GERP RS		4.7
Mutation Taster		=100/0	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: rs16866477; hg19: chr2-179596181; COSMIC: COSV99045629; COSMIC: COSV99045629;