rs766020213

Variant names:

• chr7-124824053-C-G
• rs766020213
• NM_015450.3:c.1814G>C
• POT1 p.Cys605Ser

Your query was ambiguous. Multiple possible variants found:

• chr7-124824053-C-G
• chr7-124824053-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_015450.3(POT1):​c.1814G>C​(p.Cys605Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,604,476 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. C605C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.02
• Publications: 1 publications found

Genes affected

POT1 (HGNC:17284): (protection of telomeres 1) This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

POT1 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• tumor predisposition syndrome 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• glioma susceptibility 9

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• thyroid gland carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• cerebroretinal microangiopathy with calcifications and cysts 3

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 7-124824053-C-G is Benign according to our data. Variant chr7-124824053-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 486133.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000124 (18/1452602) while in subpopulation EAS AF = 0.000458 (18/39320). AF 95% confidence interval is 0.000296. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015450.3. 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
	POT1	NM_015450.3	MANE Select	c.1814G>C	p.Cys605Ser	missense	Exon 19 of 19	NP_056265.2	Q9NUX5-1
	POT1	NM_001042594.2		c.1421G>C	p.Cys474Ser	missense	Exon 18 of 18	NP_001036059.1	A8MTK3
	POT1	NR_003102.2		n.2377G>C		non_coding_transcript_exon	Exon 20 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.1814G>C	p.Cys605Ser	missense	Exon 19 of 19	ENSP00000350249.3	Q9NUX5-1
	POT1	ENST00000607932.5	TSL:1	n.*168G>C		non_coding_transcript_exon	Exon 14 of 14	ENSP00000476506.1	Q5MJ34
	POT1	ENST00000608057.5	TSL:1	n.*911G>C		non_coding_transcript_exon	Exon 16 of 16	ENSP00000476371.1	Q5MJ35

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151874 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000739 AC: 18 AN: 243560 AF XY: 0.0000456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00100

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1452602 Hom.: 0 Cov.: 29 AF XY: 0.00000969 AC XY: 7 AN XY: 722742

African (AFR) AF: 0.00 AC: 0 AN: 33126

American (AMR) AF: 0.00 AC: 0 AN: 43868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.000458 AC: 18 AN: 39320

South Asian (SAS) AF: 0.00 AC: 0 AN: 84918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106354

Other (OTH) AF: 0.00 AC: 0 AN: 60034

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151874 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74168

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15236

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67924

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	-	1	Tumor predisposition syndrome 3 (1)
-	1	-	Tumor predisposition syndrome 3;C5830496:Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8;C5830497:Cerebroretinal microangiopathy with calcifications and cysts 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Varity_R		0.75
gMVP		0.80
Mutation Taster		=64/36	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs766020213;

hg19: chr7-124464107;