17-40657404-T-C

Variant names:

• chr17-40657404-T-C
• rs139539661
• NM_152349.3:c.607A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152349.3(KRT222):​c.607A>G​(p.Ile203Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,611,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: KRT222 NM_152349.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.311
• Publications: 0 publications found

Genes affected

KRT222 (HGNC:28695): (keratin 222) Predicted to enable structural molecule activity. Predicted to be located in intermediate filament. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000264058 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019783258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT222	NM_152349.3	c.607A>G	p.Ile203Val	missense_variant	Exon 5 of 6	ENST00000394052.5	NP_689562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT222	ENST00000394052.5	c.607A>G	p.Ile203Val	missense_variant	Exon 5 of 6	1	NM_152349.3	ENSP00000377616.3
ENSG00000264058	ENST00000476049.1	n.607A>G		non_coding_transcript_exon_variant	Exon 5 of 13	5		ENSP00000463483.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000999 AC: 25 AN: 250204 AF XY: 0.000126

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000466 AC: 68 AN: 1459054 Hom.: 0 Cov.: 30 AF XY: 0.0000606 AC XY: 44 AN XY: 725836

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39568

South Asian (SAS) AF: 0.000524 AC: 45 AN: 85816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52714

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5626

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1110856

Other (OTH) AF: 0.00 AC: 0 AN: 60284

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74340

African (AFR) AF: 0.000145 AC: 6 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.607A>G (p.I203V) alteration is located in exon 5 (coding exon 5) of the KRT222 gene. This alteration results from a A to G substitution at nucleotide position 607, causing the isoleucine (I) at amino acid position 203 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.67
DANN	Benign	0.56
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.31
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.17
Sift	Benign	0.43	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.32
MPC		0.15
ClinPred		0.017	T
GERP RS		3.4
Varity_R		0.025
gMVP		0.13
Mutation Taster		=93/7	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

Other links and lift over

dbSNP: rs139539661; hg19: chr17-38813656; COSMIC: COSV67499531; COSMIC: COSV67499531;