chr17-41034721-C-CAGCTGGTCTCACAGCAGCTTGGCTGGCAGG

Variant names:

• chr17-41034721-C-CAGCTGGTCTCACAGCAGCTTGGCTGGCAGG
• rs778448900
• NM_030966.2:c.100_101insCCTGCCAGCCAAGCTGCTGTGAGACCAGCT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4 BP6_Moderate BS2

The NM_030966.2(KRTAP1-3):​c.100_101insCCTGCCAGCCAAGCTGCTGTGAGACCAGCT​(p.Ser33_Cys34insSerCysGlnProSerCysCysGluThrSer) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.0309 in 142,046 control chromosomes in the GnomAD database, including 435 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (435 hom., cov: 32)
  • Exomes 𝑓: 0.011 (900 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP1-3 NM_030966.2 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.10
• Publications: 0 publications found

Genes affected

KRTAP1-3 (HGNC:16771): (keratin associated protein 1-3) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the high sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

ENSG00000306126 (HGNC:):

ACMG classification

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

• PM4: Nonframeshift variant in NON repetitive region in NM_030966.2.
• BP6: Variant 17-41034721-C-CAGCTGGTCTCACAGCAGCTTGGCTGGCAGG is Benign according to our data. Variant chr17-41034721-C-CAGCTGGTCTCACAGCAGCTTGGCTGGCAGG is described in ClinVar as Benign. ClinVar VariationId is 768882.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 435 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030966.2. 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
	KRTAP1-3	NM_030966.2	MANE Select	c.100_101insCCTGCCAGCCAAGCTGCTGTGAGACCAGCT	p.Ser33_Cys34insSerCysGlnProSerCysCysGluThrSer	conservative_inframe_insertion	Exon 1 of 1	NP_112228.1	Q8IUG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP1-3	ENST00000344363.7	TSL:6 MANE Select	c.100_101insCCTGCCAGCCAAGCTGCTGTGAGACCAGCT	p.Ser33_Cys34insSerCysGlnProSerCysCysGluThrSer	conservative_inframe_insertion	Exon 1 of 1	ENSP00000344420.5	Q8IUG1
	ENSG00000306126	ENST00000815517.1		n.220-25549_220-25548insGAGCTGGTCTCACAGCAGCTTGGCTGGCAG		intron	N/A
	ENSG00000306126	ENST00000815518.1		n.160-25549_160-25548insGAGCTGGTCTCACAGCAGCTTGGCTGGCAG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4381 AN: 141938 Hom.: 434 Cov.: 32

Gnomad AFR AF: 0.0750

Gnomad AMI AF: 0.0169

Gnomad AMR AF: 0.0510

Gnomad ASJ AF: 0.00919

Gnomad EAS AF: 0.0868

Gnomad SAS AF: 0.00897

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0199

Gnomad NFE AF: 0.00577

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0154 AC: 3602 AN: 234608 AF XY: 0.0132

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.0371

Gnomad ASJ exome AF: 0.00389

Gnomad EAS exome AF: 0.0786

Gnomad FIN exome AF: 0.000680

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.0148

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0109 AC: 15716 AN: 1442628 Hom.: 900 Cov.: 36 AF XY: 0.0109 AC XY: 7806 AN XY: 718156

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0589 AC: 1812 AN: 30784

American (AMR) AF: 0.0483 AC: 2026 AN: 41964

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 333 AN: 25862

East Asian (EAS) AF: 0.136 AC: 5191 AN: 38044

South Asian (SAS) AF: 0.00968 AC: 821 AN: 84856

European-Finnish (FIN) AF: 0.0166 AC: 872 AN: 52468

Middle Eastern (MID) AF: 0.0131 AC: 72 AN: 5510

European-Non Finnish (NFE) AF: 0.00319 AC: 3523 AN: 1103790

Other (OTH) AF: 0.0180 AC: 1066 AN: 59350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0309 AC: 4394 AN: 142046 Hom.: 435 Cov.: 32 AF XY: 0.0308 AC XY: 2133 AN XY: 69230

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0752 AC: 2658 AN: 35336

American (AMR) AF: 0.0509 AC: 701 AN: 13784

Ashkenazi Jewish (ASJ) AF: 0.00919 AC: 31 AN: 3374

East Asian (EAS) AF: 0.0869 AC: 384 AN: 4418

South Asian (SAS) AF: 0.00811 AC: 38 AN: 4684

European-Finnish (FIN) AF: 0.0116 AC: 119 AN: 10224

Middle Eastern (MID) AF: 0.0179 AC: 5 AN: 280

European-Non Finnish (NFE) AF: 0.00577 AC: 387 AN: 67092

Other (OTH) AF: 0.0285 AC: 56 AN: 1964

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00748 Hom.: 4

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
Mutation Taster		=68/32	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs778448900; hg19: chr17-39190973; COSMIC: COSV107427307; COSMIC: COSV107427307;