rs192528655

Variant names:

• chr2-178652905-G-A
• rs192528655
• NM_001267550.2:c.38902C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001267550.2(TTN):​c.38902C>T​(p.Pro12968Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,609,202 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00084 (10 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.930
• Publications: 2 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-178652905-G-A is Benign according to our data. Variant chr2-178652905-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238765.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000908 (138/151922) while in subpopulation SAS AF = 0.00563 (27/4792). AF 95% confidence interval is 0.00398. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.38902C>T	p.Pro12968Ser	missense	Exon 200 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34523-364C>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31742-364C>T		intron	N/A	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.38902C>T	p.Pro12968Ser	missense	Exon 200 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.38902C>T	p.Pro12968Ser	missense	Exon 200 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.38626C>T	p.Pro12876Ser	missense	Exon 198 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000909 AC: 138 AN: 151806 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00563

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00121 AC: 293 AN: 241582 AF XY: 0.00139

Gnomad AFR exome AF: 0.0000684

Gnomad AMR exome AF: 0.000572

Gnomad ASJ exome AF: 0.00693

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00108

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.000843 AC: 1229 AN: 1457280 Hom.: 10 Cov.: 34 AF XY: 0.000970 AC XY: 703 AN XY: 724904

African (AFR) AF: 0.0000909 AC: 3 AN: 33014

American (AMR) AF: 0.000615 AC: 27 AN: 43886

Ashkenazi Jewish (ASJ) AF: 0.00699 AC: 181 AN: 25896

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39548

South Asian (SAS) AF: 0.00405 AC: 347 AN: 85632

European-Finnish (FIN) AF: 0.00158 AC: 84 AN: 53172

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5720

European-Non Finnish (NFE) AF: 0.000458 AC: 508 AN: 1110306

Other (OTH) AF: 0.00108 AC: 65 AN: 60106

GnomAD4 genome AF: 0.000908 AC: 138 AN: 151922 Hom.: 0 Cov.: 31 AF XY: 0.00114 AC XY: 85 AN XY: 74250

African (AFR) AF: 0.000121 AC: 5 AN: 41446

American (AMR) AF: 0.00171 AC: 26 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00563 AC: 27 AN: 4792

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000545 AC: 37 AN: 67948

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000251 AC: 1

ExAC AF: 0.00111 AC: 134

EpiCase AF: 0.000710

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.6
DANN	Benign	0.51
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.0062	T
PhyloP100		0.93
Vest4		0.14
MVP		0.65
GERP RS		3.8
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs192528655; hg19: chr2-179517632; COSMIC: COSV105913243; COSMIC: COSV105913243;